Substituted pyrazinoquinoxaline derivatives as serotonin receptor agonist and antagonists ligands

ABSTRACT

The present invention is directed to novel compounds represented by structural Formulas (I) and (I-a):  
                 
 
     or a pharmaceutically acceptable salt thereof, wherein R 1 , R 4a , R 4b , R 5 , R 6 , R 7 , R 8 , R 9 , n, and X are described herein. The invention is also concerned with pharmaceutical formulations comprising these novel compounds as active ingredients and the use of the novel compounds and their formulations in the treatment of certain disorders. The compounds of this invention are serotonin agonists and antagonists and are useful in the control or prevention of central nervous system disorders including obesity, anxiety, depression, psychosis, schizophrenia, sleep and sexual disorders, migraine and other conditions associated with cephalic pain, social phobias, and gastrointestinal disorders such as dysfunction of the gastrointestinal tract motility.

FIELD OF THE INVENTION

[0001] The present invention is directed to novel compounds representedby structural Formulas (I) and (I-a):

[0002] or a pharmaceutically acceptable salt thereof, wherein R¹,R^(4a), R^(4b), R⁵, R⁶, R⁷, R⁸, R⁹, n, and X are described herein. Theinvention is also concerned with pharmaceutical formulations comprisingthese novel compounds as active ingredients and the use of the novelcompounds and their formulations in the treatment of certain disorders.The compounds of this invention are serotonin agonists and antagonistsand are useful in the control or prevention of central nervous systemdisorders including obesity, anxiety, depression, psychosis,schizophrenia, sleep and sexual disorders, migraine and other conditionsassociated with cephalic pain, social phobias, and gastrointestinaldisorders such as dysfunction of the gastrointestinal tract motility.

BACKGROUND OF THE INVENTION

[0003] There exists a substantial correlation for the relationshipbetween 5-HT2 receptor modulation and a variety of diseases andtherapies. To date, three subtypes of the 5-HT2 receptor class have beenidentified, 5-HT2A, 5-HT2B, and 5-HT2C. Prior to the early 1990's the5-HT2C and 5-HT2A receptors were referred to as 5-HT1C and 5-HT2,respectively.

[0004] The agonism or antagonism of 5-HT2 receptors, either selectivelyor nonselectively, has been associated with the treatment of variouscentral nervous system (CNS) disorders. Ligands possessing affinity forthe 5-HT2 receptors have been shown to have numerous physiological andbehavioral effects (Trends in Pharmacological Sciences, 11, 181, 1990).In the recent past the contribution of serotonergic activity to the modeof action of antidepressant drugs has been well documented. Compoundsthat increase the overall basal tone of serotonin in the CNS have beensuccessfully developed as antidepressants. The serotonin selectivereuptake inhibitors (SSRI) function by increasing the amount ofserotonin present in the nerve synapse. These breakthrough treatments,however, are not without side effects and suffer from delayed onset ofaction (Leonard, J. Clin. Psychiatry, 54(suppl), 3, 1993). Due to themechanism of action of the SSRIs, they effect the activity of a numberof serotonin receptor subtypes. This non-specific modulation of theserotonin family of receptors most likely plays a significant role inthe side effect profile. In addition, these compounds often have a highaffinity for a number of the serotonin receptors as well as a multitudeof other monoamine neurotransmitters and nuisance receptors. Removingsome of the receptor cross reactivity would allow for the examinationand possible development of potent therapeutic ligands with an improvedside effect profile.

[0005] There is ample evidence to support the role of selective 5-HT2receptor ligands in a number of disease therapies. Modulation of 5-HT2receptors has been associated with the treatment of schizophrenia andpsychoses (Ugedo, L., et.al., Psychopharmacology, 98, 45, 1989). Mood,behavior and hallucinogenesis can be affected by 5-HT2 receptors in thelimbic system and cerebral cortex. 5-HT2 receptor modulation in thehypothalamus can influence appetite, thermoregulation, sleep, sexualbehavior, motor activity, and neuroendocrine function (Hartig, P.,et.al., Annals New York Academy of Science, 149, 159). There is alsoevidence indicating that 5-HT2 receptors mediate hypoactivity, effectfeeding in rats, and mediate penile erections (Pyschopharmacology, 101,57, 1990).

[0006] Compounds exhibiting selectivity for the 5-HT2B receptor areuseful in treating conditions such as tachygastria, hypermotilityassociated with irritable bowel disorder, constipation, dyspepsia, andother peripherally mediated conditions.

[0007] 5-HT2A antagonists have been shown to be effective in thetreatment of schizophrenia, anxiety, depression, and migraines (Koek,W., Neuroscience and Behavioral reviews, 16, 95, 1996). Aside from thebeneficial antipsychotic effects, classical neuroleptic are frequentlyresponsible for eliciting acute extrapyramidal side effects andneuroendocrine disturbances. These compounds generally possesssignifcant dopamine D2 receptor affinity (as well as other nuisancereceptor affinity) which frequently is associated with extra pyramidalsymptoms and tardive dyskinesia, thus detracting from their efficacy asfront line treatments in schizophrenia and related disorders. Compoundspossessing a more favorable selectivity profile would represent apossible improvement for the treatment of CNS disorders.

[0008] U.S. Pat. Nos. 3,914,421; 4,013,652; 4,115,577; 4,183,936; and4,238,607 disclose pyridopyrrolobenz-heterocycles of formula:

[0009] where X is O, S, S(═O), or SO₂; n is 0 or 1; R¹ is various carbonsubstituents, and Z is a monosubstituent of H, methyl, or chloro.

[0010] U.S. Pat. No. 4,219,550 discloses pyridopyrrolo-benzheterocyclesof formula:

[0011] where X is O or S; R¹ is C₁₋₄ alkyl or cyclopropyl; R² is H, CH₃,OCH₃, Cl, Br, F, or CF₃; and (A) is —CH₂—, —CH(CH₃)—, or —CH₂CH₂—.

[0012] European Patent Application EP 473,550 A1 disclosesindolonaphthyridines of formula:

[0013] wherein X and Y are H or a simple ring, R¹, is H, alkyl,alkylcarbonylalkyl, arylcarbonylalkyl, aralkyl, or a mono ordisubstituted carbamoylalkyl; and R³, R⁴, and R⁵ are H, halogen, alkyl,alkoxy, alkylthio or trifluoromethyl.

[0014] PCT International Patent Application WO 00/35922 disclosestetrahydro-1H-pyrazino(1,2-A-quinoxalin-5(6H)one derivatives of formula:

[0015] as being 5HT2C agonists; wherein X is CR5R6 or carbonyl; R is Hor alkyl; R′ is H, alkyl, acyl , or aroyl; and R1, R2, R3, and R4 areindependently, H, alkyl, alkoxy, halogen, trifluoroalkyl, cyano,alkylsulfonamide, alkyl amide, amino, alkylamino, dialkylamino,trifluoroalkoxy, acyl, or aroyl.

[0016] None of the above references suggest or disclose the compounds ofthe present invention.

[0017] There remains a need to discover new compounds useful asserotonin agonists and antagonists which are useful in the control orprevention of central nervous system disorders. As such, the presentinvention discloses novel compounds which are of low molecular weight,useful as serotonin agonists and antagonists, and provide good in vitropotency.

SUMMARY OF THE INVENTION

[0018] One object of the present invention is to provide novel compoundswhich are useful as agonists or antagonists of 5-HT2 receptors, morespecifically 5-HT2A and 5-HT2C receptors, or pharmaceutically acceptablesalts or prodrugs thereof.

[0019] It is another object of the present invention to providepharmaceutical compositions comprising a pharmaceutically acceptablecarrier and a therapeutically effective amount of at least one of thecompounds of the present invention or a pharmaceutically acceptable saltor prodrug form thereof.

[0020] It is another object of the present invention to provide a methodfor treating central nervous system disorders including obesity,anxiety, depression, psychosis, schizophrenia, sleep and sexualdisorders, migraine and other conditions associated with cephalic pain,social phobias, and gastrointestinal disorders such as dysfunction ofthe gastrointestinal tract motility comprising administering to a hostin need of such treatment a therapeutically effective amount of at leastone of the compounds of the present invention or a pharmaceuticallyacceptable salt or prodrug form thereof. More specifically, the presentinvention provides a method for treating obesity anxiety, depression, orschizophrenia.

[0021] These and other objects, which will become apparent during thefollowing detailed description, have been achieved by the inventors'discovery that compounds of Formula (I):

[0022] or pharmaceutically acceptable salt or prodrug forms thereof,wherein R¹, R^(4a), R^(4b), R⁵, R⁶, R⁷, R⁸, and R⁹ are defined below,are effective agonists or antagonists of 5-HT2 receptors.

DETAILED DESCRIPTION OF THE EMBODIMENTS

[0023] Thus, in a first embodiment, the present invention provides anovel compound of Formula (I):

[0024] or a stereoisomer or a pharmaceutically acceptable salt formthereof, wherein:

[0025] R¹ is selected from

[0026] H,

[0027] C (═O)R²,

[0028] C (═O) OR²,

[0029] C₁₋₈ alkyl,

[0030] C₂₋₈ alkenyl,

[0031] C₂₋₈ alkynyl,

[0032] C₃₋₇ cycloalkyl,

[0033] C₁₋₆ alkyl substituted with Z,

[0034] C₂₋₆ alkenyl substituted with Z,

[0035] C₂₋₆ alkynyl substituted with Z,

[0036] C₃₋₆ alkyl substituted with Z,

[0037] aryl substituted with Z,

[0038] 5-6 membered heterocyclic ring system containing at least oneheteroatom selected from the group consisting of N, O, and S, saidheterocyclic ring system substituted with Z;

[0039] C₁₋₃ alkyl substituted with Y,

[0040] C₂₋₃ alkenyl substituted with Y,

[0041] C₂₋₃ alkynyl substituted with Y,

[0042] C₁₋₆ alkyl substituted with 0-2 R²,

[0043] C₂₋₆ alkenyl substituted with 0-2 R²,

[0044] C₂₋₆ alkynyl substituted with 0-2 R²,

[0045] aryl substituted with 0-2 R², and

[0046] 5-6 membered heterocyclic ring system containing at least oneheteroatom selected from the group consisting of N, O, and S, saidheterocyclic ring system substituted with 0-2 R²;

[0047] Y is selected from

[0048] C₃₋₆ cycloalkyl substituted with Z,

[0049] aryl substituted with Z,

[0050] 5-6 membered heterocyclic ring system containing at least oneheteroatom selected from the group consisting of N, O, and S, saidheterocyclic ring system substituted with Z;

[0051] C₃₋₆ cycloalkyl substituted with —(C₁₋₃ alkyl)-Z,

[0052] aryl substituted with —(C₁₋₃ alkyl)-Z, and

[0053] 5-6 membered heterocyclic ring system containing at least oneheteroatom selected from the group consisting of N, O, and S, saidheterocyclic ring system substituted with —(C₁₋₃ alkyl)-Z;

[0054] Z is selected from H,

[0055] —CH(OH)R²,

[0056] —C(ethylenedioxy)R²,

[0057] —OR²,

[0058] —SR²,

[0059] —NR²R³,

[0060] —C(O)R²,

[0061] —C(O)NR²R³,

[0062] —NR³C(O)R²,

[0063] —C(O) OR²,

[0064] —OC(O)R²,

[0065] —CH(═NR⁴)NR²R³,

[0066] —NHC(═NR⁴)NR²R³,

[0067] —S(O)R²,

[0068] —S(O)₂R²,

[0069] —S(O)₂NR²R³, and —NR³S(O)₂R²;

[0070] R², at each occurrence, is independently selected from

[0071] halo,

[0072] C₁₋₃ haloalkyl,

[0073] C₁₋₄ alkyl,

[0074] C₂₋₄ alkenyl,

[0075] C₂₋₄ alkynyl,

[0076] C₃₋₆ cycloalkyl,

[0077] aryl substituted with 0-5 R⁴²;

[0078] C₃₋₁₀ carbocyclic residue substituted with 0-3 R⁴¹, and

[0079] 5-10 membered heterocyclic ring system containing from 1-4heteroatoms selected from the group consisting of N, O, and Ssubstituted with 0-3 R⁴¹;

[0080] R³, at each occurrence, is independently selected from H, C₁₋₄alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, and C₁₋₄ alkoxy;

[0081] alternatively, R² and R³ join to form a 5- or 6-membered ringoptionally substituted with —O— or —N(R⁴)—;

[0082] R⁴, at each occurrence, is independently selected from H and C₁₋₄alkyl;

[0083] R^(4a) is H or C₁₋₄ alkyl;

[0084] R^(4b) is H;

[0085] alternatively, R^(4a)and R^(4b)are taken together to form ═O or═S;

[0086] R⁵ is H or C₁₋₄ alkyl;

[0087] R⁶ is H or C₁₋₄ alkyl;

[0088] alternatively, R⁵ and R⁶ are taken together to form a fusedheterocyclic ring of formula:

[0089] wherein:

[0090] X is a bond, —CH₂—, —O—, —S—, —S(═O)—, —S(═O)₂—,

[0091] —NR¹⁰—, —CH₂CH₂—, —OCH₂—, —SCH₂—, —CH₂O—, —CH₂S—,

[0092] —CH₂NR¹⁰—, —NR¹⁰CH₂—, —NHC(═O)—, or —C(═O)NH—; and

[0093] n is 1 or 2;

[0094] R⁷ and R⁹, at each occurrence, are independently selected from

[0095] H, halo, —CF₃, —OCF₃, —OH, —CN, —NO₂, —NR⁴⁶R⁴⁷,

[0096] C₁₋₈ alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, C₁₋₄ haloalkyl, C₁₋₈alkoxy, (C₁₋₄ haloalkyl)oxy,

[0097] C₃₋₁₀ cycloalkyl substituted with 0-2 R³³,

[0098] C₁₋₄ alkyl substituted with 0-2 R¹¹,

[0099] C₃₋₁₀ carbocyclic residue substituted with 0-3 R³³,

[0100] aryl substituted with 0-5 R³³,

[0101] 5-10 membered heterocyclic ring system containing from 1-4heteroatoms selected from the group consisting of N, O, and Ssubstituted with 0-3 R³¹;

[0102] OR¹², SR¹², NR¹²R¹³, C(O)H, C(O)R¹², C(O)NR¹²R¹³,

[0103] NR¹⁴C(O)R¹², C(O)OR¹², OC(O)R¹², OC(O)OR¹²,

[0104] CH(═NR¹⁴)NR¹²R¹³, NHC(═NR¹⁴)NR¹²R¹³, S(O)R¹², S(O)₂R¹²,

[0105] S(O)NR¹²R¹³, S(O)₂NR¹²R¹³, NR¹⁴S(O)R¹², NR¹⁴S(O)₂R¹²,

[0106] NR¹²C(O)R¹⁵, NR¹²C(O)OR¹⁵, NR¹²S(O)₂R¹⁵, and

[0107] NR¹²C (O) NHR¹⁵;

[0108] R⁸ is selected from

[0109] H, halo, —CF₃, —OCF₃, —OH, —CN, —NO₂,

[0110] C₁₋₈ alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, C₁₋₄ haloalkyl, C₁₋₈alkoxy, (C₁₋₄ haloalkyl)oxy, C₃₋₁₀ cycloalkyl substituted with 0-2 R³³,

[0111] C₁₋₄ alkyl substituted with 0-2 R¹¹,

[0112] C₂₋₄ alkenyl substituted with 0-2 R¹¹,

[0113] C₂₋₄ alkynyl substituted with 0-1 R¹¹,

[0114] C₃₋₁₀ carbocyclic residue substituted with 0-3 R³³,

[0115] aryl substituted with 0-5 R³³,

[0116]5-10 membered heterocyclic ring system containing from 1-4heteroatoms selected from the group consisting of N, O, and Ssubstituted with 0-3 R³¹;

[0117] OR¹², SR¹², NR¹²R¹³, C(O)H, C(O)R¹², C(O)NR¹²R¹³,

[0118] NR¹⁴C(O)R¹², C(O)OR¹², OC(O)R¹², OC(O)OR¹²,

[0119] CH(═NR¹⁴)NR¹²R¹³, NHC(═NR¹⁴)NR¹²R¹³, S(O)R¹², S(O)₂R¹²,

[0120] S(O)NR¹²R¹³, S(O)₂NR¹²R¹³, NR¹⁴S(O)R¹², NR¹⁴S(O)₂R¹²,

[0121] NR¹²C(O)R¹⁵, NR¹²C(O)OR¹⁵, NR¹²S(O)₂R¹⁵, and

[0122] NR¹²C (O)NHR¹⁵;

[0123] R¹⁰ is selected from H,

[0124] C₁₋₄ alkyl substituted with 0-2 R^(10A),

[0125] C₂₋₄ alkenyl substituted with 0-2 R^(10A),

[0126] C₂₋₄ alkynyl substituted with 0-1 R^(10A), and

[0127] C₁₋₄ alkoxy;

[0128] R^(10A) is selected from

[0129] C₁₋₄ alkoxy,

[0130] C₃₋₆ carbocyclic residue substituted with 0-3 R³³,

[0131] phenyl substituted with 0-3 R³³, and

[0132] 5-6 membered heterocyclic ring system containing 1, 2, or 3heteroatoms selected from the group consisting of N, O, and S;substituted with 0-2 R⁴⁴;

[0133] R¹¹ is selected from

[0134] H, halo, —CF₃, —CN, —NO₂,

[0135] C₁₋₈ alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, C₁₋₄ haloalkyl, C₁₋₈alkoxy, C₃₋₁₀ cycloalkyl,

[0136] C₃₋₁₀ carbocyclic residue substituted with 0-3 R³³,

[0137] aryl substituted with 0-5 R³³,

[0138] 5-10 membered heterocyclic ring system containing from 1-4heteroatoms selected from the group consisting of N, O, and Ssubstituted with 0-3 R³¹;

[0139] OR¹², SR¹², NR¹²R¹³, C(O)H, C(O)R¹², C(O)NR¹²R¹³,

[0140] NR¹⁴C(O)R¹², C(O)OR¹², OC(O)R¹², OC(O)OR¹²,

[0141] CH(═NR¹⁴)NR¹²R¹³, NHC(═NR¹⁴)NR¹²R¹³, S(O)R¹², S(O)₂R¹²,

[0142] S(O)NR¹²R¹³,S(O)₂NR¹²R¹³, NR¹⁴S(O)R¹², NR¹⁴S(O)₂R¹²,

[0143] NR¹²C(O)R¹⁵, NR¹²C(O)OR¹⁵, NR¹²S(O)₂R¹⁵, and

[0144] NR¹²C(O)NHR¹⁵;

[0145] R¹², at each occurrence, is independently selected from

[0146] C₁₋₄ alkyl substituted with 0-1 R^(12a),

[0147] C₂₋₄ alkenyl substituted with 0-1 R^(12a),

[0148] C₂₋₄ alkynyl substituted with 0-1 R^(12a),

[0149] C₃₋₆ cycloalkyl substituted with 0-3 R³³,

[0150] aryl substituted with 0-5 R³³;

[0151] C₃₋₁₀ carbocyclic residue substituted with 0-3 R³³, and

[0152] 5-10 membered heterocyclic ring system containing from 1-4heteroatoms selected from the group consisting of N, O, and Ssubstituted with 0-3 R³¹;

[0153] R^(12a), at each occurrence, is independently selected fromphenyl substituted with 0-5 R³³;

[0154] C₃₋₁₀ carbocyclic residue substituted with 0-3 R³³, and

[0155] 5-10 membered heterocyclic ring system containing from 1-4heteroatoms selected from the group consisting of N, O, and Ssubstituted with 0-3 R³¹;

[0156] R¹³, at each occurrence, is independently selected from H, C₁₋₄alkyl, C₂₋₄ alkenyl, and C₂₋₄ alkynyl;

[0157] alternatively, R¹² and R¹³ join to form a 5- or 6-membered ringoptionally substituted with —O— or —N(R¹⁴)—;

[0158] alternatively, R¹² and R¹³ when attached to N may be combined toform a 9- or 10-membered bicyclic heterocyclic ring system containingfrom 1-3 heteroatoms selected from the group consisting of N, O, and S,wherein said bicyclic heterocyclic ring system is unsaturated orpartially saturated, wherein said bicyclic heterocyclic ring system issubstituted with 0-3 R¹⁶;

[0159] R¹⁴, at each occurrence, is independently selected from H andC₁₋₄ alkyl;

[0160] R¹⁵, at each occurrence, is independently selected from H, C₁₋₄alkyl, C₂₋₄ alkenyl, and C₂₋₄ alkynyl;

[0161] R¹⁶, at each occurrence, is independently selected from H, OH,halo, CN, NO₂, CF₃, SO₂R⁴⁵, NR⁴⁶R⁴⁷, —C(═O)H, C₁₋₄ alkyl, C₂₋₄ alkenyl,C₂₋₄ alkynyl, C₁₋₄ haloalkyl, C₁₋₃ haloalkyl-oxy-, and C₁₋₃ alkyloxy-;

[0162] R³¹, at each occurrence, is independently selected from H, OH,halo, CF₃, SO₂R⁴⁵, NR⁴⁶R⁴⁷, and C₁₋₄ alkyl;

[0163] R³³, at each occurrence, is independently selected from

[0164] H, OH, halo, CN, NO₂, CF₃, SO₂R⁴⁵, NR⁴⁶R⁴⁷, —C(═O)H,

[0165] phenyl, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,

[0166] C₃₋₆ cycloalkyl, C₁₋₄ haloalkyl, C₁₋₄ haloalkyl-oxy-,

[0167] C₁₋₄ alkyloxy-, C₁₋₄ alkylthio-, C₁₋₄ alkyl-C(═O)—,

[0168] C₁₋₄ alkyl-C(═O)NH—, C₁₋₄ alkyl-OC(═O)—,

[0169] C₁₋₄ alkyl-C(═O)O—, C₃₋₆ cycloalkyl-oxy-,

[0170] C₃₋₆ cycloalkylmethyl-oxy-;

[0171] C₁₋₆ alkyl substituted with OH, methoxy, ethoxy, propoxy, butoxy,—SO₂R⁴⁵, —NR⁴⁶R⁴⁷, NR⁴⁶R⁴⁷C(═O)—, or (C₁₋₄ alkyl)CO₂—; and

[0172] C₂₋₆ alkenyl substituted with OH, methoxy, ethoxy, propoxy,butoxy, —SO₂R⁴⁵, —NR⁴⁶R⁴⁷, NR⁴⁶R⁴⁷C(═O)—, or (C₁₋₄ alkyl)CO₂—;

[0173] R⁴¹, at each occurrence, is independently selected from

[0174] H, CF₃, halo, OH, CO₂H, SO₂R⁴⁵, NR⁴⁶R⁴⁷, NO₂, CN, ═O;

[0175] C₂₋₈ alkenyl, C₂₋₈ alkynyl, C₁₋₄ alkoxy, C₁₋₄ haloalkyl

[0176] C₁₋₄ alkyl substituted with 0-1 R⁴³,

[0177] aryl substituted with 0-3 R⁴², and

[0178] 5-10 membered heterocyclic ring system containing from 1-4heteroatoms selected from the group consisting of N, O, and Ssubstituted with 0-3 R⁴⁴;

[0179] R⁴², at each occurrence, is independently selected from

[0180] H, CF₃, halo, OH, CO₂H, SO₂R⁴⁵, SOR⁴⁵, SR⁴⁵, NR⁴⁶SO₂R⁴⁵,NR⁴⁶COR⁴⁵, NR⁴⁶R⁴⁷, NO₂, CN, CH(═NH)NH₂, NHC(═NH) NH₂,

[0181] C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₄ alkoxy, C₁₋₄ haloalkyl, C₃₋₆cycloalkyl,

[0182] C₁₋₄ alkyl substituted with 0-1 R⁴³,

[0183] aryl substituted with 0-3 R⁴⁴, and

[0184] 5-10 membered heterocyclic ring system containing from 1-4heteroatoms selected from the group consisting of N, O, and Ssubstituted with 0-3 R⁴⁴;

[0185] R⁴³ is C₃₋₆ cycloalkyl or aryl substituted with 0-3 R⁴⁴;

[0186] R⁴⁴, at each occurrence, is independently selected from H, halo,—OH, NR⁴⁶R⁴⁷, CO₂H, SO₂R⁴⁵, —CF₃, —OCF₃, —CN, —NO₂, C₁₋₄ alkyl, and C₁₋₄alkoxy;

[0187] R⁴⁵ is C₁₋₄ alkyl;

[0188] R⁴⁶, at each occurrence, is independently selected from H andC₁₋₄ alkyl; and

[0189] R⁴⁷, at each occurrence, is independently selected from H, C₁₋₄alkyl, —C(═O)NH(C₁₋₄ alkyl), —SO₂(C₁₋₄ alkyl), —C(═O)O(C₁₋₄ alkyl),—C(═O) ( C₁₋₄ alkyl), and —C(═O)H;

[0190] provided when R⁵ is H or C₁₋₄ alkyl; and R⁶ is H or C₁₋₄ alkyl;then at least one of R⁷, R⁸ and R⁹ must be either 1) an aryl groupsubstituted with 1-5 R³³; 2) an arylmethyl-group substituted with 1-5R³³; or 3) —NR¹²R¹³ wherein R¹² is an aryl group substituted with 1-5R³³.

[0191] [2] In another embodiment, the present invention provides a novelcompound of Formula (I) wherein:

[0192] R¹ is selected from

[0193] H,

[0194] C(═O)R²,

[0195] C(═O)OR²,

[0196] C₁₋₈ alkyl,

[0197] C₂₋₈ alkenyl,

[0198] C₂₋₈ alkynyl,

[0199] C₃₋₇ cycloalkyl,

[0200] C₁₋₆ alkyl substituted with 0-2 R²,

[0201] C₂₋₆ alkenyl substituted with 0-2 R²,

[0202] C₂₋₆ alkynyl substituted with 0-2 R²,

[0203] aryl substituted with 0-2 R², and

[0204] 5-6 membered heterocyclic ring system containing at least oneheteroatom selected from the group consisting of N, O, and S, saidheterocyclic ring system substituted with 0-2 R²;

[0205] R², at each occurrence, is independently selected from

[0206] F, Cl, CH₂F, CHF₂, CF₃,

[0207] C₁₋₄ alkyl,

[0208] C₂₋₄ alkenyl,

[0209] C₂₋₄ alkynyl,

[0210] C₃₋₆ cycloalkyl,

[0211] phenyl substituted with 0-5 R⁴²;

[0212] C₃₋₁₀ carbocyclic residue substituted with 0-3 R⁴¹, and

[0213] 5-10 membered heterocyclic ring system containing from 1-4heteroatoms selected from the group consisting of N, O, and Ssubstituted with 0-3 R⁴¹;

[0214] R^(4a) is H or C₁₋₄ alkyl;

[0215] R^(4b) is H;

[0216] alternatively, R^(4a) and R^(4b) are taken together to form ═O or═S;

[0217] R⁵ is H or C₁₋₄ alkyl;

[0218] R⁶ is H or C₁₋₄ alkyl;

[0219] R⁷ is selected from

[0220] H, F, Cl, —CF₃, —OCF₃, —OH, —CN, —NO₂, NR¹²R¹³,

[0221] C₁₋₈ alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, C₁₋₄ haloalkyl, C₁₋₈alkoxy, (C₁₋₄ haloalkyl)oxy,

[0222] methyl substituted with R¹¹;

[0223] C₃₋₆ carbocyclic residue substituted with 0-3 R³³; and

[0224] aryl substituted with 0-5 R³³;

[0225] R⁸ is selected from

[0226] H, F, Cl, —CF₃, —OCF₃, —OH, —CN, —NO₂, NR¹²R¹³,

[0227] C₁₋₈ alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, C₁₋₄ haloalkyl, C₁₋₈alkoxy, (C₁₋₄ haloalkyl)oxy,

[0228] methyl substituted with R¹¹;

[0229] C₃₋₆ carbocyclic residue substituted with 0-3 R³³; and

[0230] aryl substituted with 0-5 R³³;

[0231] R⁹ is selected from

[0232] H, F, Cl, —CF₃, —OCF₃, —OH, —CN, —NO₂,

[0233] C₁₋₈ alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, C₁₋₄ haloalkyl, C₁₋₈alkoxy, and (C₁₋₄ haloalkyl)oxy;

[0234] R¹¹ is aryl substituted with 0-5 R³³,

[0235] R¹² is aryl substituted with 0-5 R³³,

[0236] R¹³, at each occurrence, is independently selected from H, C₁₋₄alkyl, C₂₋₄ alkenyl, and C₂₋₄ alkynyl;

[0237] alternatively, R¹² and R¹³ join to form a 5- or 6-membered ringoptionally substituted with —O— or —N(R¹⁴)—;

[0238] alternatively, R¹² and R¹³ when attached to N may be combined toform a 9- or 10-membered bicyclic heterocyclic ring system containingfrom 1-3 heteroatoms selected from the group consisting of N, O, and S,wherein said bicyclic heterocyclic ring system is unsaturated orpartially saturated, wherein said bicyclic heterocyclic ring system issubstituted with 0-3 R¹⁶;

[0239] R¹⁴, at each occurrence, is independently selected from H andC₁₋₄ alkyl; R¹⁶, at each occurrence, is independently selected from H,OH, halo, CN, NO₂, CF₃, SO₂R⁴⁵, NR⁴⁶R⁴⁷, —C(═O)H, C₁₋₄ alkyl, C₂₋₄alkenyl, C₂₋₄ alkynyl, C₁₋₄ haloalkyl, C₁₋₃ haloalkyl-oxy-, and C₁₋₃alkyloxy-;

[0240] R³³, at each occurrence, is independently selected from

[0241] H, OH, halo, CN, NO₂, CF₃, SO₂R⁴⁵, NR⁴⁶R⁴⁷, —C(═O)H,

[0242] phenyl, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,

[0243] C₃₋₆ cycloalkyl, C₁₋₄ haloalkyl, C₁₋₄ haloalkyl-oxy-,

[0244] C₁₋₄ alkyloxy-, C₁₋₄ alkylthio-, C₁₋₄ alkyl-C(═O)—,

[0245] C₁₋₄ alkyl-C(═O)NH—, C₁₋₄ alkyl-OC(═O)—,

[0246] C₁₋₄ alkyl-C(═O)O—, C₃₋₆ cycloalkyl-oxy-,

[0247] C₃₋₆ cycloalkylmethyl-oxy-;

[0248] C₁₋₆ alkyl substituted with OH, methoxy, ethoxy, propoxy, butoxy,—SO₂R⁴⁵, —NR⁴⁶R⁴⁷, NR⁴⁶R⁴⁷C(═O)—, or (C₁₋₄ alkyl)CO₂—; and

[0249] C₂₋₆ alkenyl substituted with OH, methoxy, ethoxy, propoxy,butoxy, —SO₂R⁴⁵, —NR⁴⁶R⁴⁷, NR⁴⁶R⁴⁷C(═O)—, or (C₁₋₄ alkyl)CO₂—;

[0250] R⁴¹, at each occurrence, is independently selected from

[0251] H, CF₃, halo, OH, CO₂H, SO₂R⁴⁵, NR⁴⁶R⁴⁷, NO₂, CN, ═O;

[0252] C₂₋₈ alkenyl, C₂₋₈ alkynyl, C₁₋₄ alkoxy, C₁₋₄ haloalkyl

[0253] C₁₋₄ alkyl substituted with 0-1 R⁴³,

[0254] aryl substituted with 0-3 R⁴², and

[0255] 5-10 membered heterocyclic ring system containing from 1-4heteroatoms selected from the group consisting of N, O, and Ssubstituted with 0-3 R⁴⁴ ;

[0256] R⁴², at each occurrence, is independently selected from

[0257] H, CF₃, halo, OH, CO₂H, SO₂R⁴⁵, SOR⁴⁵, SR⁴⁵, NR⁴⁶SO₂R⁴⁵,NR⁴⁶COR⁴⁵, NR⁴⁶R⁴⁷, NO₂, CN, CH(═NH)NH₂, NHC(═NH)NH₂,

[0258] C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₄ alkoxy, C₁₋₄ haloalkyl, C₃₋₆cycloalkyl,

[0259] C₁₋₄ alkyl substituted with 0-1 R⁴³,

[0260] aryl substituted with 0-3 R⁴⁴, and

[0261] 5-10 membered heterocyclic ring system containing from 1-4heteroatoms selected from the group consisting of N, O, and Ssubstituted with 0-3 R⁴⁴;

[0262] R⁴³ is C₃₋₆ cycloalkyl or aryl substituted with 0-3 R⁴⁴;

[0263] R⁴⁴, at each occurrence, is independently selected from H, halo,—OH, NR⁴⁶R⁴⁷, CO₂H, SO₂R⁴⁵, —CF₃, —OCF₃, —CN, —NO₂, C₁₋₄ alkyl, and C₁₋₄alkoxy;

[0264] R⁴⁵ is C₁₋₄ alkyl;

[0265] R⁴⁶, at each occurrence, is independently selected from H andC₁₋₄ alkyl; and

[0266] R⁴⁷, at each occurrence, is independently selected from H, C₁₋₄alkyl, —C(═O)NH(C₁₋₄ alkyl), —SO₂(C₁₋₄ alkyl), —C(═O)O(C₁₋₄ alkyl),—C(═O)( C₁₋₄ alkyl), and —C(═O)H;

[0267] provided at least one of R⁷ or R⁸ must be either 1) an aryl groupsubstituted with 1-5 R³³; 2) an arylmethyl-group substituted with 1-5R³³; or 3) —NR¹²R¹³ wherein R¹² is an aryl group substituted with 1-5R³³.

[0268] [3] In another embodiment, the present invention provides a novelcompound of Formula (I) wherein:

[0269] R¹ is selected from H,

[0270] C₁₋₅ alkyl substituted with 0-1 R²,

[0271] C₂₋₅ alkenyl substituted with 0-1 R², and

[0272] C₂₋₃ alkynyl substituted with 0-1 R²;

[0273] R² is C₃₋₆ cycloalkyl;

[0274] R^(4a) is H;

[0275] R^(4b) is H;

[0276] R⁷ is selected from

[0277] H, F, Cl, —CH₃, —OCH₃, —CF₃, —OCF₃, —CN, —NO₂, NR¹²R¹³, R¹¹;

[0278] methyl substituted with R¹¹; and

[0279] phenyl substituted with 0-2 R³³;

[0280] R⁸ is selected from

[0281] H, F, Cl, —CH₃, —OCH₃, —CF₃, —OCF₃, —CN, —NO₂, NR¹²R¹³, R¹¹;

[0282] methyl substituted with R¹¹; and

[0283] phenyl substituted with 0-2 R³³;

[0284] R⁹ is selected from

[0285] H, F, Cl, —CH₃, —OCH₃, —CF₃, —OCF₃, —CN, and —NO₂;

[0286] R¹¹ is selected from

[0287] phenyl-substituted with 0-5 fluoro;

[0288] naphthyl-substituted with 0-3 R³³;

[0289] 2-(H₃CCH₂C(═O)-phenyl-substituted with R³³;

[0290] 2-(H₃CC(═O))-phenyl-substituted with R³³;

[0291] 2-(HC(═O))-phenyl-substituted with R³³;

[0292] 2-(H₃CCH(OH))-phenyl-substituted with R³³;

[0293] 2-(H₃CCH₂CH(OH))-phenyl-substituted with R³³;

[0294] 2-(HOCH₂)-phenyl-substituted with R³³;

[0295] 2-(HOCH₂CH₂)-phenyl-substituted with R³³;

[0296] 2-(H₃COCH₂)-phenyl-substituted with R³³;

[0297] 2-(H₃COCH₂CH₂)-phenyl-substituted with R³³;

[0298] 2-(H₃CCH(OMe))-phenyl-substituted with R³³;

[0299] 2-(H₃COC(═O))-phenyl-substituted with R³³;

[0300] 2-(HOCH₂CH═CH)-phenyl-substituted with R³³;

[0301] 2-((MeOC═O)CH═CH)-phenyl-substituted with R³³;

[0302] 2-(methyl)-phenyl-substituted with R³³;

[0303] 2-(ethyl)-phenyl-substituted with R³³;

[0304] 2-(i-propyl)-phenyl-substituted with R³³;

[0305] 2-(F₃C)-phenyl-substituted with R³³;

[0306] 2-(NC)-phenyl-substituted with R³³;

[0307] 2-(H₃CO)-phenyl-substituted with R³³;

[0308] 2-(fluoro)-phenyl-substituted with R³³;

[0309] 2-(chloro)-phenyl-substituted with R³³;

[0310] 3-(NC)-phenyl-substituted with R³³;

[0311] 3-(H₃CO)-phenyl-substituted with R³³;

[0312] 3-(fluoro)-phenyl-substituted with R³³;

[0313] 3-(chloro)-phenyl-substituted with R³³;

[0314] 4-(NC)-phenyl-substituted with R³³;

[0315] 4-(fluoro)-phenyl-substituted with R³³;

[0316] 4-(chloro)-phenyl-substituted with R³³;

[0317] 4-(H₃CS)-phenyl-substituted with R³³;

[0318] 4-(H₃CO)-phenyl-substituted with R³³;

[0319] 4-(ethoxy)-phenyl-substituted with R³³;

[0320] 4-(i-propoxy)-phenyl-substituted with R³³;

[0321] 4-(i-butoxy)-phenyl-substituted with R³³;

[0322] 4-(H₃CCH₂CH₂C(═O))-phenyl-substituted with R³³;

[0323] 4-((H₃C)₂CHC(═O))-phenyl-substituted with R³³;

[0324] 4-(H₃CCH₂C(═O))-phenyl-substituted with R³³;

[0325] 4-(H₃CC(═O))-phenyl-substituted with R³³;

[0326] 4-(H₃CCH₂CH₂CH(OH))-phenyl-substituted with R³³;

[0327] 4-((H₃C)₂CHCH(OH))-phenyl-substituted with R³³;

[0328] 4-(H₃CCH₂CH(OH))-phenyl-substituted with R³³;

[0329] 4-(H₃CCH(OH))-phenyl-substituted with R³³;

[0330] 4-(cyclopropyloxy)-phenyl-substituted with R³³;

[0331] 4-(cyclobutyloxy)-phenyl-substituted with R³³; and

[0332] 4-(cyclopentyloxy)-phenyl-substituted with R³³;

[0333] R¹² is selected from

[0334] phenyl-substituted with 0-5 fluoro;

[0335] naphthyl-substituted with 0-3 R³³;

[0336] 2-(H₃CCH₂C(═O))-phenyl-substituted with R³³;

[0337] 2-(H₃CC(═O))-phenyl-substituted with R³³;

[0338] 2-(HC(═O))-phenyl-substituted with R³³;

[0339] 2-(H₃CCH(OH))-phenyl-substituted with R³³;

[0340] 2-(H₃CCH₂CH(OH))-phenyl-substituted with R³³;

[0341] 2-(HOCH₂)-phenyl-substituted with R³³;

[0342] 2-(HOCH₂CH₂)-phenyl-substituted with R³³;

[0343] 2-(H₃COCH₂)-phenyl-substituted with R³³;

[0344] 2-(H₃COCH₂CH₂)-phenyl-substituted with R³³;

[0345] 2-(H₃CCH(OMe))-phenyl-substituted with R³³;

[0346] 2-(H₃COC(═O))-phenyl-substituted with R³³;

[0347] 2-(HOCH₂CH═CH)-phenyl-substituted with R³³;

[0348] 2-((MeOC═O)CH═CH)-phenyl-substituted with R³³;

[0349] 2-(methyl)-phenyl-substituted with R³³;

[0350] 2-(ethyl)-phenyl-substituted with R³³;

[0351] 2-(i-propyl)-phenyl-substituted with R³³;

[0352] 2-(F₃C)-phenyl-substituted with R³³;

[0353] 2-(NC)-phenyl-substituted with R³³;

[0354] 2-(H₃CO)-phenyl-substituted with R³³;

[0355] 2-(fluoro)-phenyl-substituted with R³³;

[0356] 2-(choro)-phenyl-substituted with R³³;

[0357] 3-(NC)-phenyl-substituted with R³³;

[0358] 3-(H₃CO)-phenyl-substituted with R³³;

[0359] 3-(fluoro)-phenyl-substituted with R³³;

[0360] 3-(choro)-phenyl-substituted with R³³;

[0361] 4-(NC)-phenyl-substituted with R³³;

[0362] 4-(fluoro)-phenyl-substituted with R³³;

[0363] 4-(chloro)-phenyl-substituted with R³³;

[0364] 4-(H₃CS)-phenyl-substituted with R³³;

[0365] 4-(H₃CO)-phenyl-substituted with R³³;

[0366] 4-(ethoxy)-phenyl-substituted with R³³;

[0367] 4-(i-propoxy)-phenyl-substituted with R³³;

[0368] 4-(i-butoxy)-phenyl-substituted with R³³;

[0369] 4-(H₃CCH₂CH₂C(═O))-phenyl-substituted with R³³;

[0370] 4-((H₃C)₂CHC(═O))-phenyl-substituted with R³³;

[0371] 4-(H₃CCH₂C(═O))-phenyl-substituted with R³³;

[0372] 4-(H₃CC(═O))-phenyl-substituted with R³³;

[0373] 4-(H₃CCH₂CH₂CH(OH))-phenyl-substituted with R³³;

[0374] 4-((H₃C)₂CHCH(OH))-phenyl-substituted with R³³;

[0375] 4-(H₃CCH₂CH(OH))-phenyl-substituted with R³³;

[0376] 4-(H₃CCH(OH))-phenyl-substituted with R³³;

[0377] 4-(cyclopropyloxy)-phenyl-substituted with R³³;

[0378] 4-(cyclobutyloxy)-phenyl-substituted with R³³; and

[0379] 4-(cyclopentyloxy)-phenyl-substituted with R³³;

[0380] R¹³ is H, methyl, or ethyl;

[0381] alternatively, R¹² and R13 join to form a 5- or 6-membered ringselected from pyrrolyl, pyrrolidinyl, imidazolyl, piperidinyl,piperizinyl, methylpiperizinyl,and morpholinyl;

[0382] alternatively, R¹² and R¹³ when attached to N may be combined toform a 9- or 10-membered bicyclic heterocyclic ring system containingfrom 1-3 heteroatoms selected from the group consisting of N, O, and S;wherein said bicyclic heterocyclic ring system is selected from indolyl,indolinyl, indazolyl, benzimidazolyl, benzimidazolinyl, andbenztriazolyl; wherein said bicyclic heterocyclic ring system issubstituted with 0-1 R¹⁶;

[0383] R¹⁵ is H, methyl, ethyl, propyl, or butyl;

[0384] R¹⁶, at each occurrence, is independently selected from H, OH, F,Cl, CN, NO₂, methyl, ethyl, methoxy, ethoxy, trifluoromethyl, andtrifluoromethoxy; and

[0385] R³³, at each occurrence, is independently selected from

[0386] H, F, Cl, —CH₃, —OCH₃, —CF₃, —OCF₃, —CN, and —NO₂.

[0387] provided at least one of R⁷ or R⁸ must be either 1) an aryl groupsubstituted with 1-5 R³³; 2) an arylmethyl-group substituted with 1-5R³³; or 3) —NR¹²R¹³ wherein R¹² is an aryl group substituted with 1-5R³³.

[0388] [4] In another embodiment, the present invention provides a novelcompound of Formula (I) wherein:

[0389] R¹ is selected from hydrogen, methyl, ethyl, n-propyl, n-butyl,s-butyl, t-butyl, n-pentyl, n-hexyl, 2-propyl, 2-butyl, 2-pentyl,2-hexyl, 2-methylpropyl, 2-methylbutyl, 2-methylpentyl, 2-ethylbutyl,3-methylpentyl, 3-methylbutyl, 4-methylpentyl, 2-fluoroethyl,2,2-difluoroethyl, 2,2,2-trifluoroethyl, 2-propenyl,2-methyl-2-propenyl, trans-2-butenyl, 3-methyl-butenyl, 3-butenyl,trans-2-pentenyl, cis-2-pentenyl, 4-pentenyl, 4-methyl-3-pentenyl,3,3-dichloro-2-propenyl, trans-3-phenyl-2-propenyl, cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, cyclopropylmethyl,cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, —CH═CH₂,—CH₂—CH═CH₂, —CH═CH—CH₃, —C≡CH, —C≡C—CH₃, and —CH₂—C≡CH;

[0390] R^(4a) is H;

[0391] R^(4b) is H;

[0392] alternatively, R^(4a) and R^(4b) are taken together to form ═O;

[0393] R⁷ is selected from hydrogen, fluoro, chloro, bromo, cyano,methyl, ethyl, propyl, isopropyl, butyl, t-butyl, nitro,trifluoromethyl, methoxy, ethoxy, isopropoxy, and trifluoromethoxy;

[0394] R⁸ is selected from

[0395] 2-chlorophenyl, 2-fluorophenyl, 2-bromophenyl,

[0396] 2-cyanophenyl, 2-methylphenyl, 2-trifluoromethylphenyl,

[0397] 2-methoxyphenyl, 2-trifluoromethoxyphenyl,

[0398] 3-chlorophenyl, 3-fluorophenyl, 3-bromophenyl,

[0399] 3-cyanophenyl, 3-methylphenyl, 3-ethylphenyl,

[0400] 3-propylphenyl, 3-isopropylphenyl, 3-butylphenyl,

[0401] 3-trifluoromethylphenyl, 3-methoxyphenyl,

[0402] 3-isopropoxyphenyl, 3-trifluoromethoxyphenyl,

[0403] 3-thiomethoxyphenyl,

[0404] 4-chlorophenyl, 4-fluorophenyl, 4-bromophenyl,

[0405] 4-cyanophenyl, 4-methylphenyl, 4-ethylphenyl,

[0406] 4-propylphenyl, 4-isopropylphenyl, 4-butylphenyl,

[0407] 4-trifluoromethylphenyl, 4-methoxyphenyl,

[0408] 4-isopropoxyphenyl, 4-trifluoromethoxyphenyl,

[0409] 4-thiomethoxyphenyl,

[0410] 2,3-dichlorophenyl, 2,3-difluorophenyl,

[0411] 2,3-dimethylphenyl, 2,3-ditrifluoromethylphenyl,

[0412] 2,3-dimethoxyphenyl, 2,3-ditrifluoromethoxyphenyl,

[0413] 2,4-dichlorophenyl, 2,4-difluorophenyl,

[0414] 2,4-dimethylphenyl, 2,4-ditrifluoromethylphenyl,

[0415] 2,4-dimethoxyphenyl, 2,4-ditrifluoromethoxyphenyl,

[0416] 2,5-dichlorophenyl, 2,5-difluorophenyl,

[0417] 2,5-dimethylphenyl, 2,5-ditrifluoromethylphenyl,

[0418] 2,5-dimethoxyphenyl, 2,5-ditrifluoromethoxyphenyl,

[0419] 2,6-dichlorophenyl, 2,6-difluorophenyl,

[0420] 2,6-dimethylphenyl, 2,6-ditrifluoromethylphenyl,

[0421] 2,6-dimethoxyphenyl, 2,6-ditrifluoromethoxyphenyl,

[0422] 3,4-dichlorophenyl, 3,4-difluorophenyl,

[0423] 3,4-dimethylphenyl, 3,4-ditrifluoromethylphenyl,

[0424] 3,4-dimethoxyphenyl, 3,4-ditrifluoromethoxyphenyl,

[0425] 2,4,6-trichlorophenyl, 2,4,6-trifluorophenyl,

[0426] 2,4,6-trimethylphenyl, 2,4,6-tritrifluoromethylphenyl,

[0427] 2,4,6-trimethoxyphenyl, 2,4,6-tritrifluoromethoxyphenyl,

[0428] 2-chloro-4-CF₃-phenyl, 2-fluoro-3-chloro-phenyl,

[0429] 2-chloro-4-CF₃-phenyl, 2-chloro-4-methoxy-phenyl,

[0430] 2-methoxy-4-isopropyl-phenyl, 2-CF₃-4-methoxy-phenyl,

[0431] 2-methyl-4-methoxy-5-fluoro-phenyl,

[0432] 2-methyl-4-methoxy-phenyl, 2-chloro-4-CF₃O-phenyl,

[0433] 2,4,5-trimethyl-phenyl, 2-methyl-4-chloro-phenyl,

[0434] 4-acetylphenyl, 3-acetamidophenyl, 2-naphthyl;

[0435] 2-Me-5-F-phenyl, 2-F-5-Me-phenyl, 2-MeO-5-F-phenyl,

[0436] 2-Me-3-Cl-phenyl, 3-NO₂-phenyl, 2-NO₂-phenyl,

[0437] 2-Cl-3-Me-phenyl, 2-Me-4-EtO-phenyl, 2-Me-4-F-phenyl,

[0438] 2-Cl-6-F-phenyl, 2-Cl-4-(CHF₂)O-phenyl,

[0439] 2,4-diMeO-6-F-phenyl, 2-CF₃-6-F-phenyl,

[0440] 2-MeS-phenyl, 2,6-diCl-4-MeO-phenyl,

[0441] 2,3,4-triF-phenyl, 2,6-diF-4-Cl-phenyl,

[0442] 2,3,4,6-tetraF-phenyl, 2,3,4,5,6-pentaF-phenyl,

[0443] 2-CF₃-4-EtO-phenyl, 2-CF₃-4-iPrO-phenyl,

[0444] 2-CF₃-4-Cl-phenyl, 2-CF₃-4-F-phenyl, 2-Cl-4-EtO-phenyl,

[0445] 2-Cl-4-iPrO-phenyl, 2-Et-4-MeO-phenyl,

[0446] 2-CHO-4-MeO-phenyl, 2-CH₃CH(OH)-4-MeO-phenyl,

[0447] 2-CH₃CH(OH)-4-F-phenyl, 2-CH₃CH(OH)-4-Cl-phenyl,

[0448] 2-CH3CH(OH)-4-Me-phenyl, 2-CH₃CH(OMe)-4-MeO-phenyl,

[0449] 2-CH₃C(═O)-4-MeO-phenyl, 2-CH₃C(═O)-4-F-phenyl,

[0450] 2-CH₃C(═O)-4-Cl-phenyl, 2-CH₃C(═O)-4-Me-phenyl,

[0451] 2-H₂C(OH)-4-MeO-phenyl, 2-H₂C(OMe)-4-MeO-phenyl,

[0452] 2-H₃CCH₂CH(OH)-4-MeO-phenyl, 2-H₃CCH₂C(=O)-4-MeO-phenyl,

[0453] 2-CH₃CO₂CH₂CH₂-4-MeO-phenyl,

[0454] (Z)-2-HOCH₂CH═CH-4-MeO-phenyl,

[0455] (E)-2-HOCH₂CH═CH-4-MeO-phenyl,

[0456] (Z)-2-CH₃CO₂CH═CH-4-MeO-phenyl,

[0457] (E)-2-CH₃CO₂CH═CH-4-MeO-phenyl,

[0458] 2-CH₃OCH₂CH₂-4-MeO-phenyl,

[0459] 2-F-4-MeO-phenyl, 2-Cl-4-F-phenyl,

[0460] cyclohexyl, cyclopentyl, cyclohexylmethyl,

[0461] benzyl, 2-F-benzyl, 3-F-benzyl, 4-F-benzyl,

[0462] 3-MeO-benzyl, 3-OH-benzyl, 2-MeO-benzyl,

[0463] 2-OH-benzyl, 2-MeOC(═O)-3-MeO-phenyl,

[0464] 2-Me-4-CN-phenyl, 2-Me-3-CN-phenyl,

[0465] 2-Me-4-MeS-phenyl, 2-CF₃-4-CN-phenyl,

[0466] 2-CHO-phenyl, 3-CHO-phenyl, 2-HOCH₂-phenyl,

[0467] 3-HOCH₂-phenyl, 3-MeOCH₂-phenyl,

[0468] 3-Me₂NCH₂-phenyl, 3-CN-4-F-phenyl,

[0469] 2-Me-4-H₂NCO-phenyl, 2-Me-4-MeOC(═O)-phenyl,

[0470] 3-H₂NCO-4-F-phenyl, 2-Me₂NCH₂-4-MeO-phenyl-,

[0471] 2-Me-4-CH₃C(═O)-phenyl,

[0472] phenyl-NH—, (1-naphthyl)-NH—,

[0473] (2-naphthyl)-NH—, (2-[1,1′-biphenyl])-NH—,

[0474] (3-[1,1′-biphenyl])-NH—, (4-[1,1′-biphenyl])-NH—,

[0475] (2-F-phenyl)-NH—, (2-Cl-phenyl)-NH—,

[0476] (2-CF₃-phenyl)-NH—, (2-CH₃-phenyl)-NH—,

[0477] (2-OMe-phenyl)-NH—, (2-CN-phenyl)-NH—,

[0478] (2-OCF₃-phenyl)-NH—, (2-SMe-phenyl)-NH—,

[0479] (3-F-phenyl)-NH—, (3-Cl-phenyl)-NH—,

[0480] (3-CF₃-phenyl)-NH—, (3-CH₃-phenyl)-NH—,

[0481] (3-OMe-phenyl)-NH—, (3-CN-phenyl)-NH—,

[0482] (3-OCF₃-phenyl)-NH—, (3-SMe-phenyl)-NH—,

[0483] (4-F-phenyl)-NH—, (4-Cl-phenyl)-NH—,

[0484] (4-CF₃-phenyl)-NH—, (4-CH₃-phenyl)-NH—,

[0485] (4-OMe-phenyl)-NH—, (4-CN-phenyl)-NH—,

[0486] (4-OCF₃-phenyl)-NH—, (4-SMe-phenyl)-NH—,

[0487] (2,3-diCl-phenyl)-NH—, (2,4-diCl-phenyl)-NH—,

[0488] (2,5-diCl-phenyl)-NH—, (2,6-diCl-phenyl)-NH—,

[0489] (3,4-diCl-phenyl)-NH—, (3,5-diCl-phenyl)-NH—,

[0490] (2,3-diF-phenyl)-NH—, (2,4-diF-phenyl)-NH—,

[0491] (2,5-diF-phenyl)-NH—, (2,6-diF-phenyl)-NH—,

[0492] (3,4-diF-phenyl)-NH—, (3,5-diF-phenyl)-NH—,

[0493] (2,3-diCH₃-phenyl)-NH—, (2,4-diCH₃-phenyl)-NH—,

[0494] (2,5-diCH₃-phenyl)-NH—, (2,6-diCH₃-phenyl)-NH—,

[0495] (3,4-diCH₃-phenyl)-NH—, (3,5-diCH₃-phenyl)-NH—,

[0496] (2,3-diCF₃-phenyl)-NH—, (2,4-diCF₃-phenyl)-NH—,

[0497] (2,5-diCF₃-phenyl)-NH—, (2,6-diCF₃-phenyl)-NH—,

[0498] (3,4-diCF₃-phenyl)-NH—, (3,5-diCF₃-phenyl)-NH—,

[0499] (2,3-diOMe-phenyl)-NH—, (2,4-diOMe-phenyl)-NH—,

[0500] (2,5-dioMe-phenyl)-NH—, (2,6-dioMe-phenyl)-NH—,

[0501] (3,4-diOMe-phenyl)-NH—, (3,5-diOMe-phenyl)-NH—,

[0502] (2-F-3-Cl-phenyl)-NH—, (2-F-4-Cl-phenyl)-NH—,

[0503] (2-F-5-Cl-phenyl)-NH—, (2-F-6-Cl-phenyl)-NH—,

[0504] (2-F-3-CH₃-phenyl)-NH—, (2-F-4-CH₃-phenyl)-NH—,

[0505] (2-F-5-CH₃-phenyl)-NH—, (2-F-6-CH₃-phenyl)-NH—,

[0506] (2-F-3-CF₃-phenyl)-NH—, (2-F-4-CF₃-phenyl)-NH—,

[0507] (2-F-5-CF₃-phenyl)-NH—, (2-F-6-CF₃-phenyl)-NH—,

[0508] (2-F-3-OMe-phenyl)-NH—, (2-F-4-OMe-phenyl)-NH—,

[0509] (2-F-5-OMe-phenyl)-NH—, (2-F-6-OMe-phenyl)-NH—,

[0510] (2-Cl-3-F-phenyl)-NH—, (2-Cl-4-F-phenyl)-NH—,

[0511] (2-Cl-5-F-phenyl)-NH—, (2-Cl-6-F-phenyl)-NH—,

[0512] (2-Cl-3-CH₃-phenyl)-NH—, (2-Cl-4-CH₃-phenyl)-NH—,

[0513] (2-Cl-5-CH₃-phenyl)-NH—, (2-Cl-6-CH₃-phenyl)-NH—,

[0514] (2-Cl-3-CF₃-phenyl)-NH—, (2-Cl-4-CF₃-phenyl)-NH—,

[0515] (2-Cl-5-CF₃-phenyl)-NH—, (2-Cl-6-CF₃-phenyl)-NH—,

[0516] (2-Cl-3-OMe-phenyl)-NH—, (2-Cl-4-OMe-phenyl)-NH—,

[0517] (2-Cl-5-OMe-phenyl)-NH—, (2-Cl-6-OMe-phenyl)-NH—,

[0518] (2-CH₃-3-F-phenyl)-NH—, (2-CH₃-4-F-phenyl)-NH—,

[0519] (2-CH₃-5-F-phenyl)-NH—, (2-CH₃-6-F-phenyl)-NH—,

[0520] (2-CH₃-3-Cl-phenyl)-NH—, (2-CH₃-4-Cl-phenyl)-NH—,

[0521] (2-CH₃-5-Cl-phenyl)-NH—, (2-CH₃-6-Cl-phenyl)-NH—,

[0522] (2-CH₃-3-CF₃-phenyl)-NH—, (2-CH₃-4-CF₃-phenyl)-NH—,

[0523] (2-CH₃-5-CF₃-phenyl)-NH—, (2-CH₃-6-CF₃-phenyl)-NH—,

[0524] (2-CH₃-3-OMe-phenyl)-NH—, (2-CH₃-4-OMe-phenyl)-NH—,

[0525] (2-CH₃-5-OMe-phenyl)-NH—, (2-CH₃-6-OMe-phenyl)-NH—,

[0526] (2-CF₃-3-F-phenyl)-NH—, (2-CF₃-4-F-phenyl)-NH—,

[0527] (2-CF₃-5-F-phenyl)-NH—, (2-CF₃-6-F-phenyl)-NH—,

[0528] (2-CF₃-3-Cl-phenyl)-NH—, (2-CF₃-4-Cl-phenyl)-NH—,

[0529] (2-CF₃-5-Cl-phenyl)-NH—, (2-CF₃-6-Cl-phenyl)-NH—,

[0530] (2-CF₃-3-CH₃-phenyl)-NH—, (2-CF₃-4-CH₃-phenyl)-NH—,

[0531] (2-CH₃-5-CF₃-phenyl)-NH—, (2-CF₃-6-CH₃-phenyl)-NH—,

[0532] (2-CF₃-3-OMe-phenyl)-NH—, (2-CF₃-4-OMe-phenyl)-NH—,

[0533] (2-CF₃-5-OMe-phenyl)-NH—, (2-CF₃-6-OMe-phenyl)-NH—,

[0534] (2-OMe-3-F-phenyl)-NH—, (2-OMe-4-F-phenyl)-NH—,

[0535] (2-OMe-5-F-phenyl)-NH—, (2-OMe-6-F-phenyl)-NH—,

[0536] (2-OMe-3-Cl-phenyl)-NH—, (2-OMe-4-Cl-phenyl)-NH—,

[0537] (2-OMe-5-Cl-phenyl)-NH—, (2-OMe-6-Cl-phenyl)-NH—,

[0538] (2-OMe-3-CH₃-phenyl)-NH—, (2-OMe-4-CH₃-phenyl)-NH—,

[0539] (2-OMe-5-CH₃-phenyl)-NH—, (2-OMe-6-CH₃-phenyl)-NH—,

[0540] (2-OMe-3-CF₃-phenyl)-NH—, (2-OMe-4-CF₃-phenyl)-NH—,

[0541] (2-OMe-5-CF₃-phenyl)-NH—, (2-OMe-6-CF₃-phenyl)-NH—

[0542] (3-CF₃-4-Cl-phenyl)-NH—, (3-CF₃-4-C(O)CH₃-phenyl)-NH—,

[0543] (2,3,5-triCl-phenyl)-NH—, (3-CH₃-4-CO₂Me-phenyl)-NH—, and

[0544] (3-CHO-4-OMe-phenyl)-NH—; and

[0545] R⁹ is selected from hydrogen, fluoro, chloro, bromo, cyano,methyl, ethyl, propyl, isopropyl, butyl, t-butyl, nitro,trifluoromethyl, methoxy, ethoxy, isopropoxy, and trifluoromethoxy.

[0546] [5] In another embodiment, the present invention provides a novelcompound of Formula (I-a):

[0547] wherein:

[0548] X is a bond —CH₂—, —O—, —S—, —S(═O)—, —S(═O)₂—, —NR¹⁰—, —CH₂CH₂—,—OCH₂—, —SCH₂—, —CH₂O—, —CH₂S—, —NR¹⁰CH₂—, or —CH₂NR¹⁰—;

[0549] n is 1 or 2;

[0550] R¹ is selected from

[0551] H,

[0552] C(═O)R²,

[0553] C (═O) OR²,

[0554] C₁₋₈ alkyl,

[0555] C₂₋₈ alkenyl,

[0556] C₂₋₈ alkynyl,

[0557] C₃₋₇ cycloalkyl,

[0558] C₁₋₆ alkyl substituted with 0-2 R²,

[0559] C₂₋₆ alkenyl substituted with 0-2 R²,

[0560] C₂₋₆ alkynyl substituted with 0-2 R²,

[0561] aryl substituted with 0-2 R², and

[0562] 5-6 membered heterocyclic ring system containing at least oneheteroatom selected from the group consisting of N, O, and S, saidheterocyclic ring system substituted with 0-2 R²;

[0563] R², at each occurrence, is independently selected from

[0564] F, Cl, CH₂F, CHF₂, CF₃,

[0565] C₁₋₄ alkyl,

[0566] C₂₋₄ alkenyl,

[0567] C₂₋₄ alkynyl,

[0568] C₃₋₆ cycloalkyl,

[0569] phenyl substituted with 0-5 R⁴²;

[0570] C₃₋₁₀ carbocyclic residue substituted with 0-3 R⁴¹, and

[0571] 5-10 membered heterocyclic ring system containing from 1-4heteroatoms selected from the group consisting of N, O, and Ssubstituted with 0-3 R⁴¹;

[0572] R^(4a) is H or C₁₋₄ alkyl;

[0573] R^(4b) is H;

[0574] alternatively, R^(4a) and R^(4b) are taken together to form ═O or═S;

[0575] R⁷ and R⁹, at each occurrence, are independently selected from

[0576] H, halo, —CF₃, —OCF₃, —OH, —CN, —NO₂, —NR⁴⁶R⁴⁷,

[0577] C₁₋₈ alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, C₁₋₄ haloalkyl, C₁₋₈alkoxy, (C₁₋₄ haloalkyl)oxy,

[0578] C₃₋₁₀ cycloalkyl substituted with 0-2 R³³,

[0579] C₁₋₄ alkyl substituted with 0-2 R¹¹,

[0580] C₃₋₁₀ carbocyclic residue substituted with 0-3 R³³,

[0581] aryl substituted with 0-5 R³³,

[0582] 5-10 membered heterocyclic ring system containing from 1-4heteroatoms selected from the group consisting of N, O, and Ssubstituted with 0-3 R³¹;

[0583] OR¹², SR¹², NR¹²R¹³, C(O)H, C(O)R¹², C(O)NR¹²R¹³,

[0584] NR¹⁴C(O)R¹², C(O)OR¹², OC(O)R¹², OC(O)OR¹²,

[0585] CH(═NR¹⁴)NR¹²R¹³, NHC(═NR¹⁴)NR¹²R¹³, S(O)R¹², S(O)₂R¹²,

[0586] S(O)NR¹²R¹³, S(O)₂NR¹²R¹³, NR¹⁴S(O)R¹², NR¹⁴S(O)₂R¹² ,

[0587] NR¹²C(O)R¹⁵, NR¹²C(O)OR¹⁵, NR¹²S(O)₂R¹⁵, and

[0588] NR¹²C(O)NHR¹⁵;

[0589] R⁸ is selected from

[0590] H, halo, —CF₃, —OCF₃, —OH, —CN, —NO₂,

[0591] C₁₋₈ alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, C₁₋₄ haloalkyl, C₁₋₈alkoxy, (C₁₋₄ haloalkyl)oxy,

[0592] C₃₋₁₀ cycloalkyl substituted with 0-2 R³³,

[0593] C₁₋₄ alkyl substituted with 0-2 R¹¹,

[0594] C₂₋₄ alkenyl substituted with 0-2 R¹¹,

[0595] C₂₋₄ alkynyl substituted with 0-1 R¹¹,

[0596] C₃₋₁₀ carbocyclic residue substituted with 0-3 R³³,

[0597] aryl substituted with 0-5 R³³,

[0598] 5-10 membered heterocyclic ring system containing from 1-4heteroatoms selected from the group consisting of N, O, and Ssubstituted with 0-3 R³¹;

[0599] OR¹², SR¹², NR¹²R¹³, C(O)H, C(O)R¹², C(O)NR¹²R¹³,

[0600] NR¹⁴C(O)R¹², C(O)OR¹², OC(O)R¹², OC(O)OR¹²,

[0601] CH(═NR¹⁴)NR¹²R¹³, NHC(═NR¹⁴)NR¹²R¹³, S(O)R¹², S(O)₂R¹²,

[0602] S(O)NR¹²R¹³, S(O)₂NR¹²R¹³, NR¹⁴S(O)R¹², NR¹⁴S(O)₂R¹²,

[0603] NR¹²C(O)R¹⁵, NR¹²C(O)OR¹⁵, NR¹²S(O)₂R¹⁵, and

[0604] NR¹²C(O)NHR¹⁵;

[0605] R¹⁰ is selected from H, C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl,and C₁₋₄ alkoxy;

[0606] R¹¹ is selected from

[0607] H, halo, —CF₃, —CN, —NO₂,

[0608] C₁₋₈ alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, C₁₋₄ haloalkyl, C₁₋₈alkoxy, C₃₋₁₀ cycloalkyl,

[0609] C₃₋₁₀ carbocyclic residue substituted with 0-3 R³³,

[0610] aryl substituted with 0-5 R³³,

[0611] 5-10 membered heterocyclic ring system containing from 1-4heteroatoms selected from the group consisting of N, O, and Ssubstituted with 0-3 R³¹;

[0612] OR¹², SR¹², NR¹²R¹³, C(O)H, C(O)R¹², C(O)NR¹²R¹³,

[0613] NR¹⁴C(O)R¹², C(O)OR¹², OC(O)R¹², OC(O)OR¹²,

[0614] CH(═NR¹⁴)NR¹²R¹³, NHC(═NR¹⁴)NR¹²R¹³, S(O)R¹², S(O)₂R¹²,

[0615] S(O)NR¹²R¹³, S(O)₂NR¹²R¹³, NR¹⁴S(O)R¹², NR¹⁴S(O)₂R¹²,

[0616] NR¹²C(O)R¹⁵, NR¹²C(O)OR¹⁵, NR¹²S(O)₂R¹⁵, and

[0617] NR¹²C (O)NHR¹⁵;

[0618] R¹², at each occurrence, is independently selected from

[0619] C₁₋₄ alkyl substituted with 0-1 R^(12a),

[0620] C₂₋₄ alkenyl substituted with 0-1 R^(12a),

[0621] C₂₋₄ alkynyl substituted with 0-1 R^(12a),

[0622] C₃₋₆ cycloalkyl substituted with 0-3 R³³,

[0623] aryl substituted with 0-5 R³³;

[0624] C₃₋₁₀ carbocyclic residue substituted with 0-3 R³³, and

[0625] 5-10 membered heterocyclic ring system containing from 1-4heteroatoms selected from the group consisting of N, O, and Ssubstituted with 0-3 R³¹;

[0626] R^(12a), at each occurrence, is independently selected fromphenyl substituted with 0-5 R³³;

[0627] C₃₋₁₀ carbocyclic residue substituted with 0-3 R³³, and

[0628] 5-10 membered heterocyclic ring system containing from 1-4heteroatoms selected from the group consisting of N, O, and Ssubstituted with 0-3 R³¹.

[0629] R¹³, at each occurrence, is independently selected from H, C₁₋₄alkyl, C₂₋₄ alkenyl, and C₂₋₄ alkynyl;

[0630] alternatively, R¹² and R¹³ join to form a 5- or 6-membered ringoptionally substituted with —O— or —N(R¹⁴)—;

[0631] alternatively, R¹² and R¹³ when attached to N may be combined toform a 9- or 10-membered bicyclic heterocyclic ring system containingfrom 1-3 heteroatoms selected from the group consisting of N, O, and S,wherein said bicyclic heterocyclic ring system is unsaturated orpartially saturated, wherein said bicyclic heterocyclic ring system issubstituted with 0-3 R¹⁶;

[0632] R¹⁴, at each occurrence, is independently selected from H andC₁₋₄ alkyl;

[0633] R¹⁵, at each occurrence, is independently selected from H, C₁₋₄alkyl, C₂₋₄ alkenyl, and C₂₋₄ alkynyl;

[0634] R¹⁶, at each occurrence, is independently selected from H, OH,halo, CN, NO₂, CF₃, SO₂R⁴⁵, NR⁴⁶R⁴⁷, —C(═O)H, C₁₋₄ alkyl, C₂₋₄ alkenyl,C₂₋₄ alkynyl, C₁₋₄ haloalkyl, C₁₋₃ haloalkyl-oxy-, and C₁₋₃ alkyloxy-;

[0635] R³¹, at each occurrence, is independently selected from H, OH,halo, CF₃, SO₂R⁴⁵, NR⁴⁶R⁴⁷, and C₁₋₄ alkyl;

[0636] R³³, at each occurrence, is independently selected from

[0637] H, OH, halo, CN, NO₂, CF₃, SO₂R⁴⁵, NR⁴⁶R⁴⁷, —C(═O)H, phenyl, C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,

[0638] C₃₋₆ cycloalkyl, C₁₋₄ haloalkyl, C₁₋₄ haloalkyl-oxy-,

[0639] C₁₋₄ alkyloxy-, C₁₋₄ alkylthio-, C₁₋₄ alkyl-C(═O)—,

[0640] C₁₋₄ alkyl-C(═O)NH—, C₁₋₄ alkyl-OC(═O)—,

[0641] C₁₋₄ alkyl-C(═O)O—, C₃₋₆ cycloalkyl-oxy-,

[0642] C₃₋₆ cycloalkylmethyl-oxy-;

[0643] C₁₋₆ alkyl substituted with OH, methoxy, ethoxy, propoxy, butoxy,—SO₂R⁴⁵, —NR⁴⁶R⁴⁷, NR⁴⁶R⁴⁷C(═O)—, or (C₁₋₄ alkyl)CO₂—; and

[0644] C₂₋₆ alkenyl substituted with OH, methoxy, ethoxy, propoxy,butoxy, —SO₂R⁴⁵, —NR⁴⁶R⁴⁷, NR⁴⁶R⁴⁷C(═O)—, or (C₁₋₄ alkyl)CO₂—;

[0645] R⁴¹, at each occurrence, is independently selected from

[0646] H, CF₃, halo, OH, CO₂H, SO₂R⁴⁵, NR⁴⁶R⁴⁷, NO₂, CN;

[0647] C₂₋₈ alkenyl, C₂₋₈ alkynyl, C₁₋₄ alkoxy, C₁₋₄ haloalkyl

[0648] C₁₋₄ alkyl substituted with 0-1 R⁴³,

[0649] aryl substituted with 0-3 R⁴², and

[0650] 5-10 membered heterocyclic ring system containing from 1-4heteroatoms selected from the group consisting of N, O, and Ssubstituted with 0-3 R⁴⁴;

[0651] R⁴², at each occurrence, is independently selected from

[0652] H, CF₃, halo, OH, CO₂H, SO₂R⁴⁵, NR⁴⁶R⁴⁷, NO₂, CN, CH(═NH)NH₂,NHC(═NH)NH₂,

[0653] C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₄ alkoxy, C₁₋₄ haloalkyl, C₃₋₆cycloalkyl,

[0654] C₁₋₄ alkyl substituted with 0-1 R⁴³,

[0655] aryl substituted with 0-3 R⁴⁴, and

[0656] 5-10 membered heterocyclic ring system containing from 1-4heteroatoms selected from the group consisting of N, O, and Ssubstituted with 0-3 R⁴⁴ ;

[0657] R⁴³ is C₃₋₆ cycloalkyl or aryl substituted with 0-3 R⁴⁴;

[0658] R⁴⁴, at each occurrence, is independently selected from H, halo,—OH, NR⁴⁶R⁴⁷, CO₂H, SO₂R⁴⁵, —CF₃, —OCF₃, —CN, —NO₂, C₁₋₄ alkyl, and C₁₋₄alkoxy;

[0659] R⁴⁵ is C₁₋₄ alkyl;

[0660] R⁴⁶, at each occurrence, is independently selected from H andC₁₋₄ alkyl; and

[0661] R⁴⁷, at each occurrence, is independently selected from H andC₁₋₄ alkyl.

[0662] [6] In another embodiment, the present invention provides a novelcompound of Formula (I-b):

[0663] wherein:

[0664] X is —CH₂—, —O—, —S—, —CH₂CH₂—, —OCH₂—, —SCH₂—, —CH₂O—, or—CH₂S—;

[0665] R¹ is selected from

[0666] H,

[0667] C(═O) R²,

[0668] C(═O)OR²,

[0669] C₁₋₆ alkyl,

[0670] C₂₋₆ alkenyl,

[0671] C₂₋₆ alkynyl,

[0672] C₃₋₆ cycloalkyl,

[0673] C₁₋₄ alkyl substituted with 0-2 R²,

[0674] C₂₋₄ alkenyl substituted with 0-2 R², and

[0675] C₂₋₄ alkynyl substituted with 0-2 R²;

[0676] R², at each occurrence, is independently selected from

[0677] C₁₋₄ alkyl,

[0678] C₂₋₄ alkenyl,

[0679] C₂₋₄ alkynyl,

[0680] C₃₋₆ cycloalkyl,

[0681] phenyl substituted with 0-5 R⁴²;

[0682] C₃₋₁₀ carbocyclic residue substituted with 0-3 R⁴¹, and

[0683] 5-10 membered heterocyclic ring system containing from 1-4heteroatoms selected from the group consisting of N, O, and Ssubstituted with 0-3 R⁴¹;

[0684] R^(4a) is H or C₁₋₄ alkyl;

[0685] R^(4b) is H;

[0686] alternatively, R^(4a) and R^(4b) are taken together to form ═O or═S;

[0687] R⁷ and R⁹, at each occurrence, are independently selected from

[0688] H, halo, —CF₃, —OCF₃, —OH, —CN, —NO₂, —NR⁴⁶R⁴⁷,

[0689] C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₁₋₆alkoxy, (C₁₋₄ haloalkyl)oxy,

[0690] C₃₋₁₀ cycloalkyl substituted with 0-2 R³³,

[0691] C₁₋₄ alkyl substituted with 0-2 R¹¹,

[0692] C₃₋₁₀ carbocyclic residue substituted with 0-3 R³³,

[0693] aryl substituted with 0-5 R³³,

[0694] 5-10 membered heterocyclic ring system containing from 1-4heteroatoms selected from the group consisting of N, O, and Ssubstituted with 0-3 R³¹;

[0695] OR¹², SR¹², NR¹²R¹³, C(O)H, C(O)R¹², C(O)NR¹²R¹³, NR¹⁴C(O)R¹²,C(O)OR¹², OC(O)R¹², OC(O)OR¹², CH(═NR¹⁴)NR¹²R^(l3), NHC(═NR¹⁴)NR¹²R¹³,S(O)R¹², S(O)₂R¹², S(O)NR¹²R¹³, S(O)₂NR¹²R^(l3), NR¹⁴S(O)R¹², andNR¹⁴S(O)₂R¹²;

[0696] R⁸ is selected from

[0697] H, halo, —CF₃, —OCF₃, —OH, —CN, —NO₂,

[0698] C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₁₋₆alkoxy, (C₁₋₄ haloalkyl)oxy,

[0699] C₃₋₁₀ cycloalkyl substituted with 0-2 R³³,

[0700] C₁₋₄ alkyl substituted with 0-2 R¹¹,

[0701] C₂₋₄ alkenyl substituted with 0-2 R¹¹,

[0702] C₂₋₄ alkynyl substituted with 0-1 R¹¹,

[0703] C₃₋₁₀ carbocyclic residue substituted with 0-3 R³³,

[0704] aryl substituted with 0-5 R³³,

[0705]5-10 membered heterocyclic ring system containing from 1-4heteroatoms selected from the group consisting of N, O, and Ssubstituted with 0-3 R³¹;

[0706] OR¹², SR¹², NR¹²R¹³, C(O)H, C(O)R¹², C(O)NR¹²R¹³,

[0707] NR¹⁴C(O)R¹², C(O)OR¹², OC(O)R¹², OC(O)OR¹²,

[0708] CH(═NR¹⁴)NR¹²R¹³, NHC(═NR¹⁴) NR¹²R¹³, S(O)R¹², S(O)₂R¹²,

[0709] S(O)NR¹²R¹³, S(O)₂NR¹²R¹³, NR¹⁴S(O)R¹², NR¹⁴S(O)₂R¹²,

[0710] NR¹²C(O)R¹⁵, NR¹²C(O)OR¹⁵, NR¹²S(O)₂R¹⁵, and

[0711] NR¹²C(O)NHR¹⁵;

[0712] R¹¹ is selected from

[0713] H, halo, —CF₃, —CN, —NO₂, C₁₋₆ alkyl,

[0714] C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₄ haloalkyl, C₁₋₆ alkoxy, C₃₋₁₀cycloalkyl,

[0715] C₃₋₁₀ carbocyclic residue substituted with 0-3 R³³,

[0716] aryl substituted with 0-5 R³³,

[0717] 5-10 membered heterocyclic ring system containing from 1-4heteroatoms selected from the group consisting of N, O, and Ssubstituted with 0-3 R³¹;

[0718] OR¹², SR¹², NR¹²R¹³, C(O)H, C(O)R¹², C(O)NR¹²R¹³, NR¹⁴C(O)R¹²,C(O)OR¹², OC(O)R¹², OC(O)OR¹², CH(═NR¹⁴)NR¹²R¹³, NHC(═NR¹⁴)NR¹²R¹³,S(O)R¹², S(O)₂R¹², S(O)NR¹²R¹³, S(O)₂NR¹²R¹³, NR¹⁴S(O)R¹², andNR¹⁴S(O)₂R¹²;

[0719] R¹², at each occurrence, is independently selected from

[0720] C₁₋₄ alkyl substituted with 0-1 R^(12a),

[0721] C₂₋₄ alkenyl substituted with 0-1 R^(12a),

[0722] C₂₋₄ alkynyl substituted with 0-1 R^(12a),

[0723] C₃₋₆ cycloalkyl substituted with 0-3 R³³,

[0724] aryl substituted with 0-5 R³³;

[0725] C₃₋₁₀ carbocyclic residue substituted with 0-3 R³³, and

[0726] 5-10 membered heterocyclic ring system containing from 1-4heteroatoms selected from the group consisting of N, O, and Ssubstituted with 0-3 R³¹;

[0727] R^(12a), at each occurrence, is independently selected from

[0728] phenyl substituted with 0-5 R³³;

[0729] C₃₋₁₀ carbocyclic residue substituted with 0-3 R³³, and

[0730] 5-10 membered heterocyclic ring system containing from 1-4heteroatoms selected from the group consisting of N, O, and Ssubstituted with 0-3 R³¹;

[0731] R¹³, at each occurrence, is independently selected from H, C₁₋₄alkyl, C₂₋₄ alkenyl, and C₂₋₄ alkynyl;

[0732] alternatively, R¹² and R¹³ join to form a 5- or 6-membered ringoptionally substituted with —O— or —N(R¹⁴)—;

[0733] alternatively, R¹² and R¹³ when attached to N may be combined toform a 9- or 10-membered bicyclic heterocyclic ring system containingfrom 1-3 heteroatoms selected from the group consisting of N, O, and S,wherein said bicyclic heterocyclic ring system is unsaturated orpartially saturated, wherein said bicyclic heterocyclic ring system issubstituted with 0-3 R¹⁶;

[0734] R¹⁴, at each occurrence, is independently selected from H,methyl, ethyl, propyl, and butyl;

[0735] R¹⁵, at each occurrence, is independently selected from H, C₁₋₄alkyl, C₂₋₄ alkenyl, and C₂₋₄ alkynyl;

[0736] R¹⁶, at each occurrence, is independently selected from H, OH, F,Cl, CN, NO₂, CF₃, SO₂R⁴⁵, NR⁴⁶R⁴⁷, —C(═O)H, methyl, ethyl, methoxy,ethoxy, trifluoromethyl, and trifluoromethoxy;

[0737] R³¹, at each occurrence, is independently selected from H, OH,halo, CF₃, SO₂R⁴⁵, NR⁴⁶R⁴⁷, and C₁₋₄ alkyl;

[0738] R³³, at each occurrence, is independently selected from

[0739] H, OH, halo, CN, NO₂, CF₃, SO₂R⁴⁵, NR⁴⁶R⁴⁷, —C(═O)H,

[0740] phenyl, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,

[0741] C₃₋₆ cycloalkyl, C₁₋₄ haloalkyl, C₁₋₄ haloalkyl-oxy-,

[0742] C₁₋₄ alkyloxy-, C₁₋₄ alkylthio-, C₁₋₄ alkyl-C(═O)—,

[0743] C₁₋₄ alkyl-C(═O)NH—, C₁₋₄ alkyl-OC(═O)—,

[0744] C₁₋₄ alkyl-C(═O)O—, C₃₋₆ cycloalkyl-oxy-,

[0745] C₃₋₆ cycloalkylmethyl-oxy-;

[0746] C₁₋₆ alkyl substituted with OH, methoxy, ethoxy, propoxy, butoxy,—SO₂R⁴⁵, —NR⁴⁶R⁴⁷, NR⁴⁶R⁴⁷C(═O)—, or (C₁₋₄ alkyl)CO₂—; and

[0747] C₂₋₆ alkenyl substituted with OH, methoxy, ethoxy, propoxy,butoxy, —SO₂R⁴⁵, —NR⁴⁶R⁴⁷, NR⁴⁶R⁴⁷C(═O)—, or (C₁₋₄ alkyl)CO₂—;

[0748] R⁴¹, at each occurrence, is independently selected from

[0749] H, CF₃, halo, OH, CO₂H, SO₂R⁴⁵, NR⁴⁶R⁴⁷, NO₂, CN,

[0750] C₂₋₈ alkenyl, C₂₋₈ alkynyl, C₁₋₄ alkoxy, C₁₋₄ haloalkyl

[0751] C₁₋₄ alkyl substituted with 0-1 R⁴³,

[0752] aryl substituted with 0-3 R⁴², and

[0753] 5-10 membered heterocyclic ring system containing from 1-4heteroatoms selected from the group consisting of N, O, and Ssubstituted with 0-3 R⁴⁴;

[0754]⁴², at each occurrence, is independently selected from

[0755] H, CF₃, halo, OH, CO₂H, SO₂R⁴⁵, NR⁴⁶R⁴⁷, NO₂, CN, CH(═NH)NH₂,NHC(═NH)NH₂,

[0756] C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₄ alkoxy, C₁₋₄ haloalkyl, C₃₋₆cycloalkyl,

[0757] C₁₋₄ alkyl substituted with 0-1 R⁴³,

[0758] aryl substituted with 0-3 R⁴⁴, and

[0759] 5-10 membered heterocyclic ring system containing from 1-4heteroatoms selected from the group consisting of N, O, and Ssubstituted with 0-3 R⁴⁴;

[0760] R⁴³ is C₃₋₆ cycloalkyl or aryl substituted with 0-3 R⁴⁴;

[0761] R⁴⁴, at each occurrence, is independently selected from H, halo,—OH, NR⁴⁶R⁴⁷, CO₂H, SO₂R⁴⁵, —CF₃, —OCF₃, —CN, —NO₂, C₁₋₄ alkyl, and C₁₋₄alkoxy;

[0762] R⁴⁵ is C₁₋₄ alkyl;

[0763] R⁴⁶, at each occurrence, is independently selected from H andC₁₋₄ alkyl; and

[0764] R⁴⁷, at each occurrence, is independently selected from H andC₁₋₄ alkyl.

[0765] [7] In another embodiment, the present invention provides a novelcompound of Formula (I-b):

[0766] wherein:

[0767] X is —CH₂—, —O—, —S—, —CH₂CH₂—, —OCH₂—, or —SCH₂—;

[0768] R¹ is selected from

[0769] H,

[0770] C₁₋₄ alkyl,

[0771] C₂₋₄ alkenyl,

[0772] C₂₋₄ alkynyl,

[0773] C₃₋₄ cycloalkyl,

[0774] C₁₋₃ alkyl substituted with 0-1 R²,

[0775] C₂₋₃ alkenyl substituted with 0-1 R², and

[0776] C₂₋₃ alkynyl substituted with 0-1 R²;

[0777] R², at each occurrence, is independently selected from

[0778] C₁₋₄ alkyl,

[0779] C₂₋₄ alkenyl,

[0780] C₂₋₄ alkynyl,

[0781] C₃₋₆ cycloalkyl,

[0782] phenyl substituted with 0-5 R⁴²;

[0783] C₃₋₆ carbocyclic residue substituted with 0-3 R⁴¹, and

[0784] 5-6 membered heterocyclic ring system containing 1, 2, or 3heteroatoms selected from the group consisting of N, O, and Ssubstituted with 0-3 R⁴¹;

[0785] R^(4a) is H, methyl, ethyl, propyl, or butyl;

[0786] R^(4b) is H;

[0787] alternatively, R^(4a) and R^(4b) are taken together to form ═O or═S;

[0788] R⁷ and R⁹, at each occurrence, are independently selected from

[0789] H, halo, —CF₃, —OCF₃, —OH, —CN, —NO₂, —NR⁴⁶R⁴⁷,

[0790] C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, C₁₋ ₄ haloalkyl,

[0791] C₁₋₄ alkoxy, (C₁₋₄ haloalkyl)oxy,

[0792] C₃₋₁₀ cycloalkyl substituted with 0-2 R³³,

[0793] C₁₋₄ alkyl substituted with 0-2 R¹¹,

[0794] C₃₋₁₀ carbocyclic residue substituted with 0-3 R³³,

[0795] aryl substituted with 0-5 R³³, and

[0796] 5-6 membered heterocyclic ring system containing 1, 2, or 3heteroatoms selected from the group consisting of N, O, and Ssubstituted with 0-3 R³¹;

[0797] R⁸ is selected from

[0798] H, halo, —CF₃, —OCF₃, —OH, —CN, —NO₂,

[0799] C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, C₁₋₄ haloalkyl, C₁₋₄alkoxy, (C₁₋₄ haloalkyl)oxy,

[0800] C₃₋₁₀ cycloalkyl substituted with 0-2 R³³,

[0801] C₁₋₄ alkyl substituted with 0-2 R¹¹,

[0802] C₂₋₄ alkenyl substituted with 0-2 R¹¹,

[0803] C₂₋₄ alkynyl substituted with 0-1 R¹¹,

[0804] C₃₋₁₀ carbocyclic residue substituted with 0-3 R³³,

[0805] aryl substituted with 0-5 R³³,

[0806] 5-6 membered heterocyclic ring system containing 1, 2, or 3heteroatoms selected from the group consisting of N, O, and Ssubstituted with 0-3 R³¹;

[0807] OR¹², SR¹², NR¹²R¹³, NR₁₂C(O)R¹⁵, NR¹²C(O)OR¹⁵, NR¹²S(O)₂R¹⁵, andNR¹²C(O)NHR¹⁵;

[0808] R¹¹ is selected from

[0809] H, halo, —CF₃, —CN, —NO₂,

[0810] C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, C₁₋₄ haloalkyl, C₁₋₄alkoxy, (C₁₋₄ haloalkyl)oxy,

[0811] C₃₋₁₀ cycloalkyl substituted with 0-2 R³³,

[0812] C₃₋₁₀ carbocyclic residue substituted with 0-3 R³³,

[0813] aryl substituted with 0-5 R³³, and

[0814] 5-6 membered heterocyclic ring system containing 1, 2, or 3heteroatoms selected from the group consisting of N, O, and Ssubstituted with 0-3 R³¹;

[0815] R¹², at each occurrence, is independently selected from

[0816] C₁₋₄ alkyl substituted with 0-1 R^(12a),

[0817] C₂₋₄ alkenyl substituted with 0-1 R^(12a),

[0818] C₂₋₄ alkynyl substituted with 0-1 R^(12a),

[0819] C₃₋₆ cycloalkyl substituted with 0-3 R³³,

[0820] aryl substituted with 0-5 R³³;

[0821] C₃₋₁₀ carbocyclic residue substituted with 0-3 R³³, and

[0822] 5-10 membered heterocyclic ring system containing from 1-4heteroatoms selected from the group consisting of N, O, and Ssubstituted with 0-3 R³¹;

[0823] R^(12a), at each occurrence, is independently selected fromphenyl substituted with 0-5 R³³;

[0824] C₃₋₁₀ carbocyclic residue substituted with 0-3 R³³, and

[0825] 5-10 membered heterocyclic ring system containing from 1-4heteroatoms selected from the group consisting of N, O, and Ssubstituted with 0-3 R³¹;

[0826] R¹³, at each occurrence, is independently selected from H, C₁₋₄alkyl, C₂₋₄ alkenyl, and C₂₋₄ alkynyl;

[0827] alternatively, R¹² and R¹³ join to form a 5- or 6-membered ringoptionally substituted with —O— or —N(R¹⁴)—;

[0828] alternatively, R¹² and R¹³ when attached to N may be combined toform a 9- or 10-membered bicyclic heterocyclic ring system containingfrom 1-3 heteroatoms selected from the group consisting of one N, two N,three N, one N one O, and one N one S; wherein said bicyclicheterocyclic ring system is unsaturated or partially saturated, whereinsaid bicyclic heterocyclic ring system is substituted with 0-2 R¹⁶;

[0829] R¹⁴, at each occurrence, is independently selected from H,methyl, ethyl, propyl, and butyl;

[0830] R¹⁵, at each occurrence, is independently selected from H,methyl, ethyl, propyl, and butyl;

[0831] R¹⁶, at each occurrence, is independently selected from H, OH, F,Cl, CN, NO₂, methyl, ethyl, methoxy, ethoxy, trifluoromethyl, andtrifluoromethoxy;

[0832] R³¹, at each occurrence, is independently selected from H, OH,halo, CF₃, methyl, ethyl, and propyl;

[0833] R³³, at each occurrence, is independently selected from

[0834] H, OH, halo, CN, NO₂, CF₃, SO₂R⁴⁵, NR⁴⁶R⁴⁷, —C(═O)H,

[0835] phenyl, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,

[0836] C₃₋₆ cycloalkyl, C₁₋₄ haloalkyl, C₁₋₄ haloalkyl-oxy-,

[0837] C₁₋₄ alkyloxy-, C₁₋₄ alkylthio-, C₁₋₄ alkyl-C(═O)—,

[0838] C₁₋₄ alkyl-C(═O)NH—, C₁₋₄ alkyl-OC(═O)—,

[0839] C₁₋₄ alkyl-C(═O)O—, C₃₋₆ cycloalkyl-oxy-,

[0840] C₃₋₆ cycloalkylmethyl-oxy-;

[0841] C₁₋₆ alkyl substituted with OH, methoxy, ethoxy, propoxy, butoxy,—SO₂R⁴⁵, —NR⁴⁶R⁴⁷, NR⁴⁶R⁴⁷C(═O)—, or (C₁₋₄ alkyl)CO₂—; and

[0842] C₂₋₆ alkenyl substituted with OH, methoxy, ethoxy, propoxy,butoxy, —SO₂R⁴⁵, —NR⁴⁶R⁴⁷, NR⁴⁶R⁴⁷C(═O)—, or (C₁₋₄ alkyl)CO₂—;

[0843] R⁴¹, at each occurrence, is independently selected from H, CF₃,halo, OH, CO₂H, SO₂R⁴⁵, NR⁴⁶R⁴⁷, NO₂, CN, C₂₋₄ alkenyl, C₂₋ ₄ alkynyl,C₁₋₃ alkoxy, C₁₋₃ haloalkyl, and C₁₋₃ alkyl;

[0844] R⁴², at each occurrence, is independently selected from

[0845] H, CF₃, halo, OH, CO₂H, SO₂R⁴⁵, NR⁴⁶R⁴⁷, NO₂, CN, CH(═NH)NH₂,NHC(═NH)NH₂,

[0846] C₂₋₄ alkenyl, C₂₋₄ alkynyl, C₁₋₃ alkoxy, C₁₋₃ haloalkyl, C₃₋₆cycloalkyl, and C₁₋₃ alkyl;

[0847] R⁴³ is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl,or pyridyl, each substituted with 0-3 R⁴⁴;

[0848] R⁴⁴, at each occurrence, is independently selected from H, halo,—OH, NR⁴⁶R⁴⁷, CO₂H, SO₂R⁴⁵, —CF₃, —OCF₃, —CN, —NO₂, methyl, ethyl,propyl, butyl, methoxy, ethoxy, propoxy, and butoxy;

[0849] R⁴⁵ is methyl, ethyl, propyl, or butyl;

[0850] R⁴⁶, at each occurrence, is independently selected from H,methyl, ethyl, propyl, and butyl; and

[0851] R⁴⁷, at each occurrence, is independently selected from from H,methyl, ethyl, propyl, and butyl.

[0852] [8] In another embodiment, the present invention provides a novelcompound of Formula (I-b):

[0853] X is —CH₂—, —O— or —S—;

[0854] R¹ is selected from

[0855] H,

[0856] C₁₋₄ alkyl,

[0857] C₂₋₄ alkenyl,

[0858] C₂₋₄ alkynyl,

[0859] C₃₋₄ cycloalkyl,

[0860] C₁₋₃ alkyl substituted with 0-1 R²,

[0861] C₂₋₃ alkenyl substituted with 0-1 R², and

[0862] C₂₋₃ alkynyl substituted with 0-1 R²;

[0863] R², at each occurrence, is independently selected from

[0864] C₁₋₄ alkyl,

[0865] C₂₋₄ alkenyl,

[0866] C₂₋₄ alkynyl,

[0867] C₃₋₆ cycloalkyl,

[0868] phenyl substituted with 0-5 R⁴²;

[0869] C₃₋₆ carbocyclic residue substituted with 0-3 R⁴¹, and

[0870] 5-6 membered heterocyclic ring system containing 1, 2, or 3heteroatoms selected from the group consisting of N, O, and Ssubstituted with 0-3 R⁴¹;

[0871] R^(4a) is H;

[0872] R^(4b) is H;

[0873] alternatively, R^(4a) and R^(4b) are taken together to form ═O;

[0874] R⁷ and R⁹, at each occurrence, are independently selected from

[0875] H, F, Cl, —CH₃, —OCH₃, —CF₃, —OCF₃, —CN, and —NO₂,

[0876] R⁸ is selected from

[0877] H, F, Cl, Br, —CF₃, —OCF₃, —OH, —CN, —NO₂,

[0878] C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, C₁₋₄ haloalkyl, C₁₋₄alkoxy, (C₁₋₄ haloalkyl)oxy,

[0879] C₃₋₁₀ cycloalkyl substituted with 0-2 R³³,

[0880] C₁₋₄ alkyl substituted with 0-2 R¹¹,

[0881] C₂₋₄ alkenyl substituted with 0-2 R¹¹,

[0882] C₂₋₄ alkynyl substituted with 0-1 R¹¹,

[0883] C₃₋₁₀ carbocyclic residue substituted with 0-3 R³³,

[0884] aryl substituted with 0-5 R³³,

[0885] 5-6 membered heterocyclic ring system containing 1, 2, or 3heteroatoms selected from the group consisting of N, O, and Ssubstituted with 0-3 R³¹;

[0886] OR¹², SR¹², NR¹²R¹³, NR¹²C(O)R¹⁵, NR¹²C(O)OR¹⁵, NR¹²S(O)₂R¹⁵, andNR¹²C(O)NHR¹⁵;

[0887] R¹¹ is selected from

[0888] H, halo, —CF₃, —CN, —NO₂,

[0889] C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, C₁₋₄ haloalkyl, C₁₋₄alkoxy, (C₁₋₄ haloalkyl)oxy,

[0890] C₃₋₁₀ cycloalkyl substituted with 0-2 R³³,

[0891] C₃₋₁₀ carbocyclic residue substituted with 0-3 R³³,

[0892] aryl substituted with 0-5 R³³, and

[0893] 5-6 membered heterocyclic ring system containing 1, 2, or 3heteroatoms selected from the group consisting of N, O, and Ssubstituted with 0-3 R³¹;

[0894] R¹², at each occurrence, is independently selected from

[0895] C₁₋₄ alkyl substituted with 0-1 R^(12a),

[0896] C₂₋₄ alkenyl substituted with 0-1 R^(12a),

[0897] C₂₋₄ alkynyl substituted with 0-1 R^(12a),

[0898] C₃₋₆ cycloalkyl substituted with 0-3 R³³,

[0899] aryl substituted with 0-5 R³³;

[0900] C₃₋₁₀ carbocyclic residue substituted with 0-3 R³³, and

[0901] 5-10 membered heterocyclic ring system containing from 1-4heteroatoms selected from the group consisting of N, O, and Ssubstituted with 0-3 R³¹;

[0902] R^(12a), at each occurrence, is independently selected fromphenyl substituted with 0-5 R³³;

[0903] C₃₋₁₀ carbocyclic residue substituted with 0-3 R³³, and

[0904] 5-10 membered heterocyclic ring system containing from 1-4heteroatoms selected from the group consisting of N, O, and Ssubstituted with 0-3 R³¹;

[0905] R¹³, at each occurrence, is independently selected from H, C₁₋₄alkyl, C₂₋₄ alkenyl, and C₂₋₄ alkynyl;

[0906] alternatively, R¹² and R¹³ join to form a 5- or 6-membered ringoptionally substituted with —O— or —N(R¹⁴)—;

[0907] alternatively, R¹² and R¹³ when attached to N may be combined toform a 9- or 10-membered bicyclic heterocyclic ring system containingfrom 1-3 heteroatoms selected from the group consisting of N, O, and S;wherein said bicyclic heterocyclic ring system is selected from indolyl,indolinyl, indazolyl, benzimidazolyl, benzimidazolinyl, andbenztriazolyl; wherein said bicyclic heterocyclic ring system issubstituted with 0-1 R¹⁶;

[0908] R¹⁴, at each occurrence, is independently selected from H,methyl, ethyl, propyl, and butyl;

[0909] R¹⁵, at each occurrence, is independently selected from H,methyl, ethyl, propyl, and butyl;

[0910] R¹⁶, at each occurrence, is independently selected from H, OH, F,Cl, CN, NO₂, methyl, ethyl, methoxy, ethoxy, trifluoromethyl, andtrifluoromethoxy;

[0911] R³¹, at each occurrence, is independently selected from H, OH,halo, CF₃, methyl, ethyl, and propyl;

[0912] R³³, at each occurrence, is independently selected from

[0913] H, OH, halo, CN, NO₂, CF₃, SO₂R⁴⁵, NR⁴⁶R⁴⁷, —C(═O)H,

[0914] phenyl, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,

[0915] C₃₋₆ cycloalkyl, C₁₋₄ haloalkyl, C₁₋₄ haloalkyl-oxy-,

[0916] C₁₋₄ alkyloxy-, C₁₋₄ alkylthio-, C₁₋₄ alkyl-C(═O)—,

[0917] C₁₋₄ alkyl-C(═O)NH—, C₁₋₄ alkyl-OC(═O)—,

[0918] C₁₋₄ alkyl-C(═O)O—, C₃₋₆ cycloalkyl-oxy-,

[0919] C₃₋₆ cycloalkylmethyl-oxy-;

[0920] C₁₋₆ alkyl substituted with OH, methoxy, ethoxy, propoxy, butoxy,—SO₂R⁴⁵, —NR⁴⁶R⁴⁷, NR⁴⁶R⁴⁷C(═O)—, or (C₁₋₄ alkyl)CO₂—; and

[0921] C₂₋₆ alkenyl substituted with OH, methoxy, ethoxy, propoxy,butoxy, —SO₂R⁴⁵, —NR⁴⁶R⁴⁷, NR⁴⁶R⁴⁷C(═O)—, or (C₁₋₄ alkyl)CO₂—;

[0922] R⁴¹, at each occurrence, is independently selected from

[0923] H, CF₃, halo, OH, CO₂H, SO₂R⁴⁵, NR⁴⁶R⁴⁷, NO₂, CN,

[0924] C₂₋₄ alkenyl, C₂₋₄ alkynyl, C₁₋₃ alkoxy, C₁₋₃ haloalkyl, and C₁₋₃alkyl;

[0925] R⁴², at each occurrence, is independently selected from

[0926] H, CF₃, halo, OH, CO₂H, SO₂R⁴⁵, NR⁴⁶R⁴⁷, NO₂, CN, CH(═NH)NH₂,NHC(═NH)NH₂,

[0927] C₂₋₄ alkenyl, C₂₋₄ alkynyl, C₁₋₃ alkoxy, C₁₋₃ haloalkyl, C₃₋₆cycloalkyl, and C₁₋₃ alkyl;

[0928] R⁴³ is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl,or pyridyl, each substituted with 0-3 R⁴⁴;

[0929] R⁴⁴, at each occurrence, is independently selected from H, halo,—OH, NR⁴⁶R⁴⁷, CO₂H, SO₂R⁴⁵, —CF₃, —OCF₃, —CN, —NO₂, methyl, ethyl,propyl, butyl, methoxy, ethoxy, propoxy, and butoxy;

[0930] R⁴⁵ is methyl, ethyl, propyl, or butyl;

[0931] R⁴⁶, at each occurrence, is independently selected from H,methyl, ethyl, propyl, and butyl; and

[0932] R⁴⁷, at each occurrence, is independently selected from from H,methyl, ethyl, propyl, and butyl.

[0933] [9] In another embodiment, the present invention provides a novelcompound of Formula (I-b):

[0934] X is —CH₂—, —O—, or —S—;

[0935] R¹ is selected from H,

[0936] C₁₋₅ alkyl substituted with 0-1 R²,

[0937] C₂₋₅ alkenyl substituted with 0-1 R², and

[0938] C₂₋₃ alkynyl substituted with 0-1 R²;

[0939] R² is C₃₋₆ cycloalkyl;

[0940] R^(4a) is H;

[0941] R^(4b) is H;

[0942] R⁷ and R⁹, at each occurrence, are independently selected from H,F, Cl, —CH₃, —OCH₃, —CF₃, —OCF₃, —CN, and —NO₂;

[0943] R⁸ is selected from R¹¹;

[0944] methyl substituted with R¹¹;

[0945] phenyl substituted with 0-2 R³³;

[0946] OR¹², SR¹², NR¹²R¹³, NR¹²C(O) R¹⁵, NR¹²C(O)OR¹⁵, NR¹²S(O)₂R¹⁵,and NR¹²C(O)NHR¹⁵;

[0947] R¹l is selected from

[0948] phenyl-substituted with 0-5 fluoro;

[0949] naphthyl-substituted with 0-3 R³³;

[0950] 2-(H₃CCH₂C(═O))-phenyl-substituted with R³³;

[0951] 2-(H₃CC(═O))-phenyl-substituted with R³³;

[0952] 2-(HC(═O))-phenyl-substituted with R³³;

[0953] 2-(H₃CCH(OH))-phenyl-substituted with R³³;

[0954] 2-(H₃CCH₂CH(OH))-phenyl-substituted with R³³;

[0955] 2-(HOCH₂)-phenyl-substituted with R³³;

[0956] 2-(HOCH₂CH₂)-phenyl-substituted with R³³;

[0957] 2-(H₃COCH₂)-phenyl-substituted with R³³;

[0958] 2-(H₃COCH₂CH₂)-phenyl-substituted with R³³;

[0959] 2-(H₃CCH(OMe))-phenyl-substituted with R³³;

[0960] 2-(H₃COC(═O))-phenyl-substituted with R³³;

[0961] 2-(HOCH₂CH═CH)-phenyl-substituted with R³³;

[0962] 2-((MeOC═O)CH═CH)-phenyl-substituted with R³³;

[0963] 2-(methyl)-phenyl-substituted with R³³;

[0964] 2-(ethyl)-phenyl-substituted with R³³;

[0965] 2-(i-propyl)-phenyl-substituted with R³³;

[0966] 2-(F₃C)-phenyl-substituted with R³³;

[0967] 2-(NC)-phenyl-substituted with R³³;

[0968] 2-(H₃CO)-phenyl-substituted with R³³;

[0969] 2-(fluoro)-phenyl-substituted with R³³;

[0970] 2-(chloro)-phenyl-substituted with R³³;

[0971] 3-(NC)-phenyl-substituted with R³³;

[0972] 3-(H₃CO)-phenyl-substituted with R³³;

[0973] 3-(fluoro)-phenyl-substituted with R³³;

[0974] 3-(chloro)-phenyl-substituted with R³³;

[0975] 4-(NC)-phenyl-substituted with R³³;

[0976] 4-(fluoro)-phenyl-substituted with R³³;

[0977] 4-(chloro)-phenyl-substituted with R³³;

[0978] 4-(H₃CS)-phenyl-substituted with R³³;

[0979] 4-(H₃CO)-phenyl-substituted with R³³;

[0980] 4-(ethoxy)-phenyl-substituted with R³³;

[0981] 4-(i-propoxy)-phenyl-substituted with R³³;

[0982] 4-(i-butoxy)-phenyl-substituted with R³³;

[0983] 4-(H₃CCH₂CH₂C(═O))-phenyl-substituted with R³³;

[0984] 4-((H₃C)₂CHC(═O))-phenyl-substituted with R³³;

[0985] 4-(H₃CCH₂C(═O))-phenyl-substituted with R³³;

[0986] 4-(H₃CC(═O))-phenyl-substituted with R³³;

[0987] 4-(H₃CCH₂CH₂CH(OH))-phenyl-substituted with R³³;

[0988] 4-(H₃C)₂CHCH (OH))-phenyl-substituted with R³³;

[0989] 4-(H₃CCH₂CH (OH))-phenyl-substituted with R³³;

[0990] 4-(H₃CCH(OH))-phenyl-substituted with R³³;

[0991] 4-(cyclopropyloxy)-phenyl-substituted with R³³;

[0992] 4-(cyclobutyloxy)-phenyl-substituted with R³³; and

[0993] 4-(cyclopentyloxy)-phenyl-substituted with R³³;

[0994] R¹² is selected from

[0995] phenyl-substituted with 0-5 fluoro;

[0996] naphthyl-substituted with 0-3 R³³;

[0997] 2-(H₃CCH₂C(═O))-phenyl-substituted with R³³;

[0998] 2-(H₃CC(═O))-phenyl-substituted with R³³;

[0999] 2-(HC(═O))-phenyl-substituted with R³³;

[1000] 2-(H₃CCH(OH))-phenyl-substituted with R³³;

[1001] 2-(H₃CCH₂CH (OH))-phenyl-substituted with R³³;

[1002] 2-(HOCH₂)-phenyl-substituted with R³³;

[1003] 2-(HOCH₂CH₂)-phenyl-substituted with R³³;

[1004] 2-(H₃COCH₂)-phenyl-substituted with R³³;

[1005] 2-(H₃COCH₂CH₂)-phenyl-substituted with R³³;

[1006] 2-(H₃CCH(OMe))-phenyl-substituted with R³³;

[1007] 2-(H₃COC(═O))-phenyl-substituted with R³³;

[1008] 2-(HOCH₂CH═CH)-phenyl-substituted with R³³;

[1009] 2-((MeOC=O)CH═CH)-phenyl-substituted with R³³;

[1010] 2-(methyl)-phenyl-substituted with R³³;

[1011] 2-(ethyl)-phenyl-substituted with R³³;

[1012] 2-(i-propyl)-phenyl-substituted with R³³;

[1013] 2-(F₃C)-phenyl-substituted with R³³;

[1014] 2-(NC)-phenyl-substituted with R³³;

[1015] 2-(H₃CO)-phenyl-substituted with R³³;

[1016] 2-(fluoro)-phenyl-substituted with R³³;

[1017] 2-(chloro)-phenyl-substituted with R³³;

[1018] 3-(NC)-phenyl-substituted with R³³;

[1019] 3-(H₃CO)-phenyl-substituted with R³³;

[1020] 3-(fluoro)-phenyl-substituted with R³³;

[1021] 3-(chloro)-phenyl-substituted with R³³;

[1022] 4-(NC)-phenyl-substituted with R³³;

[1023] 4-(fluoro)-phenyl-substituted with R³³;

[1024] 4-(chloro)-phenyl-substituted with R³³;

[1025] 4-((H₃CS)-phenyl-substituted with R³³;

[1026] 4-(H₃CO)-phenyl-substituted with R³³;

[1027] 4-(ethoxy)-phenyl-substituted with R³³;

[1028] 4-(i-propoxy)-phenyl-substituted with R³³;

[1029] 4-(i-butoxy)-phenyl-substituted with R³³;

[1030] 4-(H₃CCH₂CH₂C(═O))-phenyl-substituted with R³³;

[1031] 4-((H₃C)₂CHC(═O))-phenyl-substituted with R³³;

[1032] 4-(H₃CCH₂CH(═O))-phenyl-substituted with R³³;

[1033] 4-(H₃CC(═O))-phenyl-substituted with R³³;

[1034] 4-(H₃CCH₂CH₂CH(OH))-phenyl-substituted with R³³;

[1035] 4-((H₃C)₂CHCH(OH))-phenyl-substituted with R³³;

[1036] 4-(H₃CCH₂CH(OH))-phenyl-substituted with R³³;

[1037] 4-(H₃CCH(OH))-phenyl-substituted with R³³;

[1038] 4-(cyclopropyloxy)-phenyl-substituted with R³³;

[1039] 4-(cyclobutyloxy)-phenyl-substituted with R³³; and

[1040] 4-(cyclopentyloxy)-phenyl-substituted with R³³;

[1041] R¹³ is H, methyl, or ethyl;

[1042] alternatively, R¹² and R¹³ join to form a 5- or 6-membered ringselected from pyrrolyl, pyrrolidinyl, imidazolyl, piperidinyl,piperizinyl, methylpiperizinyl,and morpholinyl;

[1043] alternatively, R¹² and R¹³ when attached to N may be combined toform a 9- or 10-membered bicyclic heterocyclic ring system containingfrom 1-3 heteroatoms selected from the group consisting of N, O, and S;wherein said bicyclic heterocyclic ring system is selected from indolyl,indolinyl, indazolyl, benzimidazolyl, benzimidazolinyl, andbenztriazolyl; wherein said bicyclic heterocyclic ring system issubstituted with 0-1 R¹⁶;

[1044] R¹⁵ is H, methyl, ethyl, propyl, or butyl;

[1045] R¹⁶, at each occurrence, is independently selected from H, OH, F,Cl, CN, NO₂, methyl, ethyl, methoxy, ethoxy, trifluoromethyl, andtrifluoromethoxy; and

[1046] R³³, at each occurrence, is independently selected from H, F, Cl,—CH₃, —OCH₃, —CF₃, —OCF₃, —CN, and —NO₂.

[1047] [10] In another embodiment, the present invention provides anovel compound of Formula (I-b):

[1048] wherein:

[1049] R¹ is selected from hydrogen, methyl, ethyl, n-propyl, n-butyl,s-butyl, t-butyl, n-pentyl, n-hexyl, 2-propyl, 2-butyl, 2-pentyl,2-hexyl, 2-methylpropyl, 2-methylbutyl, 2-methylpentyl, 2-ethylbutyl,3-methylpentyl, 3-methylbutyl, 4-methylpentyl, 2-fluoroethyl,2,2-difluoroethyl, 2,2,2-trifluoroethyl, 2-propenyl,2-methyl-2-propenyl, trans-2-butenyl, 3-methyl-butenyl, 3-butenyl,trans-2-pentenyl, cis-2-pentenyl, 4-pentenyl, 4-methyl-3-pentenyl,3,3-dichloro-2-propenyl, trans-3-phenyl-2-propenyl, cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, cyclopropylmethyl,cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, —CH═CH₂,—CH₂—CH═CH₂, —CH═CH—CH₃, —C≡CH, —C≡C—CH₃, and —CH₂—C≡CH;

[1050] R^(4a) is H;

[1051] R^(4b) is H;

[1052] alternatively, R^(4a) and R^(4b) are taken together to form ═O;

[1053] R⁷ and R⁹, at each occurrence, are independently selected fromhydrogen, fluoro, methyl, trifluoromethyl, and methoxy;

[1054] R⁸ is selected from

[1055] hydrogen, fluoro, chloro, bromo, cyano, methyl, ethyl,

[1056] propyl, isopropyl, butyl, t-butyl, nitro,

[1057] trifluoromethyl, methoxy, ethoxy, isopropoxy,

[1058] trifluoromethoxy, phenyl,

[1059] methylC(═O)—, ethylC(═O)—, propylC(═O)—, isopropylC(═O)—,

[1060] butylC(═O)—, phenylC(═O)—,

[1061] methylCO₂—, ethylCO₂—, propylCO₂—, isopropylCO₂—,

[1062] butylCO₂—, phenylCO₂—,

[1063] dimethylamino-S(═O)—, diethylamino-S(═O)—,

[1064] dipropylamino-S(═O)—, di-isopropylamino-S(═O)—,

[1065] dibutylamino-S(═O)—, diphenylamino-S(═O)—,

[1066] dimethylamino-SO₂—, diethylamino-SO₂—,

[1067] dipropylamino-SO₂—, di-isopropylamino-SO₂—,

[1068] dibutylamino-SO₂—, diphenylamino-SO₂—,

[1069] dimethylamino-C(═O)—, diethylamino-C(═O)—,

[1070] dipropylamino-C(═O)—, di-isopropylamino-C(═O)—,

[1071] dibutylamino-C(═O)—, diphenylamino-C(═O)—,

[1072] 2-chlorophenyl, 2-fluorophenyl, 2-bromophenyl,

[1073] 2-cyanophenyl, 2-methylphenyl, 2-trifluoromethylphenyl,

[1074] 2-methoxyphenyl, 2-trifluoromethoxyphenyl,

[1075] 3-chlorophenyl, 3-fluorophenyl, 3-bromophenyl,

[1076] 3-cyanophenyl, 3-methylphenyl, 3-ethylphenyl,

[1077] 3-propylphenyl, 3-isopropylphenyl, 3-butylphenyl,

[1078] 3-trifluoromethylphenyl, 3-methoxyphenyl,

[1079] 3-isopropoxyphenyl, 3-trifluoromethoxyphenyl,

[1080] 3-thiomethoxyphenyl,

[1081] 4-chlorophenyl, 4-fluorophenyl, 4-bromophenyl,

[1082] 4-cyanophenyl, 4-methylphenyl, 4-ethylphenyl,

[1083] 4-propylphenyl, 4-isopropylphenyl, 4-butylphenyl,

[1084] 4-trifluoromethylphenyl, 4-methoxyphenyl,

[1085] 4-isopropoxyphenyl, 4-trifluoromethoxyphenyl,

[1086] 4-thiomethoxyphenyl,

[1087] 2,3-dichlorophenyl, 2,3-difluorophenyl,

[1088] 2,3-dimethylphenyl, 2,3-ditrifluoromethylphenyl,

[1089] 2,3-dimethoxyphenyl, 2,3-ditrifluoromethoxyphenyl,

[1090] 2,4-dichlorophenyl, 2,4-difluorophenyl,

[1091] 2,4-dimethylphenyl, 2,4-ditrifluoromethylphenyl,

[1092] 2,4-dimethoxyphenyl, 2,4-ditrifluoromethoxyphenyl,

[1093] 2,5-dichlorophenyl, 2,5-difluorophenyl,

[1094] 2,5-dimethyphenyl, 2,5-ditrifluoromethylphenyl,

[1095] 2,5-dimethoxyphenyl, 2,5-ditrifluoromethoxyphenyl,

[1096] 2,6-dichlorophenyl, 2,6-difluorophenyl,

[1097] 2,6-dimethylphenyl, 2,6-ditrifluoromethylphenyl,

[1098] 2,6-dimethoxyphenyl, 2,6-ditrifluoromethoxyphenyl,

[1099] 3,4-dichlorophenyl, 3,4-difluorophenyl,

[1100] 3,4-dimethylphenyl, 3,4-ditrifluoromethylphenyl,

[1101] 3,4-dimethoxyphenyl, 3,4-ditrifluoromethoxyphenyl,

[1102] 2,4,6-trichlorophenyl , 2,4,6-trifluorophenyl,

[1103] 2,4,6-trimethylphenyl , 2,4,6-tritrifluoromethylphenyl ,

[1104] 2,4,6-trimethoxyphenyl, 2,4,6-tritrifluoromethoxyphenyl ,

[1105] 2-chloro-4-CF₃-phenyl, 2-fluoro-3-chloro-phenyl,

[1106] 2-chloro-4-CF₃-phenyl, 2-chloro-4-methoxy-phenyl,

[1107] 2-methoxy-4-isopropyl-phenyl, 2-CF₃-4-methoxy-phenyl,

[1108] 2-methyl-4-methoxy-5-fluoro-phenyl,

[1109] 2-methyl-4-methoxy-phenyl, 2-chloro-4-CF₃O-phenyl,

[1110] 2,4,5-trimethyl-phenyl, 2-methyl-4-chloro-phenyl,

[1111] methyl-C(═O)NH—, ethyl-C(═O)NH—, propyl-C(═O)NH—,

[1112] isopropyl-C(═O)NH—, butyl-C(═O)NH—, phenyl-C(═O)NH—,

[1113] 4-acetylphenyl, 3-acetamidophenyl, 4-pyridyl, 2-furanyl,

[1114] 2-thiophenyl, 2-naphthyl;

[1115] 2-Me-5-F-phenyl, 2-F-5-Me-phenyl, 2-MeO-5-F-phenyl,

[1116] 2-Me-3-Cl-phenyl, 3-NO₂-phenyl, 2-NO₂-phenyl,

[1117] 2-Cl-3-Me-phenyl, 2-Me-4-EtO-phenyl, 2-Me-4-F-phenyl,

[1118] 2-Cl-6-F-phenyl, 2-Cl-4-(CHF₂)O-phenyl,

[1119] 2,4-diMeO-6-F-phenyl, 2-CF₃-6-F-phenyl,

[1120] 2-MeS-phenyl, 2,6-diCl-4-MeO-phenyl,

[1121] 2,3,4-triF-phenyl, 2,6-diF-4-Cl-phenyl,

[1122] 2,3,4,6-tetraF-phenyl, 2,3,4,5,6-pentaF-phenyl,

[1123] 2-CF₃-4-EtO-phenyl, 2-CF₃-4-iPrO-phenyl,

[1124] 2-CF₃-4-Cl-phenyl, 2-CF₃-4-F-phenyl, 2-Cl-4-EtO-phenyl,

[1125] 2-Cl-4-iPrO-phenyl, 2-Et-4-MeO-phenyl,

[1126] 2-CHO-4-MeO-phenyl, 2-CH₃CH(OH)-4-MeO-phenyl,

[1127] 2-CH₃CH(OH)-4-F-phenyl, 2-CH₃CH(OH)-4-Cl-phenyl,

[1128] 2-CH₃CH(OH)-4-Me-phenyl, 2-CH₃CH(OMe)-4-MeO-phenyl,

[1129] 2-CH₃C(═O)-4-MeO-phenyl, 2-CH₃C(═O)-4-F-phenyl,

[1130] 2-CH₃C(═O)-4-Cl-phenyl, 2-CH₃C(═O)-4-Me-phenyl,

[1131] 2-H₂C(OH)-4-MeO-phenyl, 2-H₂C(OMe)-4-MeO-phenyl,

[1132] 2-H₃CCH₂CH(OH)-4-MeO-phenyl, 2-H₃CCH₂C(═O)-4-MeO-phenyl,

[1133] 2-CH₃CO₂CH₂CH₂-4-MeO-phenyl,

[1134] (Z)-2-HOCH₂CH═CH-4-MeO-phenyl,

[1135] (E)-2-HOCH₂CH=CH-4-MeO-phenyl,

[1136] (Z)-2-CH₃CO₂CH═CH-4-MeO-phenyl,

[1137] (E)-2-CH₃CO₂CH═CH-4-MeO-phenyl,

[1138] 2-CH₃OCH₂CH₂-4-MeO-phenyl,

[1139] 2-F-4-MeO-phenyl, 2-Cl-4-F-phenyl,

[1140] (2-Cl-phenyl)-CH═CH—, (3-Cl-phenyl)-CH═CH—,

[1141] (2,6-diF-phenyl)-CH═CH—, —CH₂CH═CH₂,

[1142] phenyl-CH═CH—, (2-Me-4-MeO-phenyl)-CH═CH—,

[1143] cyclohexyl, cyclopentyl, cyclohexylmethyl,

[1144] EtCO₂CH₂CH₂—, EtCO₂CH₂CH₂CH₂—, EtCO₂CH₂CH₂CH₂CH₂—,

[1145] benzyl, 2-F-benzyl, 3-F-benzyl, 4-F-benzyl,

[1146] 3-MeO-benzyl, 3-OH-benzyl, 2-MeO-benzyl,

[1147] 2-OH-benzyl, 2-MeOC(═O)-3-MeO-phenyl,

[1148] 2-Me-4-CN-phenyl, 2-Me-3-CN-phenyl,

[1149] 2-Me-4-MeS-phenyl, 2-CF₃-4-CN-phenyl,

[1150] 2-CHO-phenyl, 3-CHO-phenyl, 2-HOCH₂-phenyl,

[1151] 3-HOCH₂ -phenyl, 3-MeOCH₂ -phenyl,

[1152] 3-Me₂NCH₂-phenyl, 3-CN-4-F-phenyl,

[1153] 2-Me-4-H₂NCO-phenyl, 2-Me-4-MeOC(═O)-phenyl,

[1154] 3-H₂NCO-4-F-phenyl, 2-Me₂NCH₂-4-MeO-phenyl-,

[1155] 2-Me-4-CH₃C(═O)-phenyl, phenyl-S—, Me₂N—,

[1156] 1-pyrrolidinyl,

[1157] phenyl-NH—, benzyl-NH—, (1-naphthyl)-NH—,

[1158] (2-naphthyl)-NH—, (2-[1,1′-biphenyl])-NH—,

[1159] (3-[1,1′-biphenyl])-NH—, (4-[1,1′-biphenyl])-NH—,

[1160] (2-F-phenyl)-NH—, (2-Cl-phenyl)-NH—,

[1161] (2-CF₃-phenyl)-NH—, (2-CH₃-phenyl)-NH—,

[1162] (2-OMe-phenyl)-NH—, (2-CN-phenyl)-NH—,

[1163] (2-OCF₃-phenyl)-NH—, (2-SMe-phenyl)-NH—,

[1164] (3-F-phenyl)-NH—, (3-Cl-phenyl)-NH—,

[1165] (3- CF3-phenyl)-NH—, (3-CH₃-phenyl)-NH—,

[1166] (3-OMe-phenyl)-NH—, (3-CN-phenyl)-NH—,

[1167] (3-OCF₃-phenyl)-NH—, (3-SMe-phenyl)-NH—,

[1168] (4-F-phenyl)-NH—, (4-Cl-phenyl)-NH—,

[1169] (4-CF₃-phenyl)-NH—, (4-CH₃-phenyl)-NH—,

[1170] (4-OMe-phenyl)-NH—, (4-CN-phenyl)-NH—,

[1171] (4-OCF₃-phenyl)-NH—, (4-SMe-phenyl)-NH—,

[1172] (2,3-diCl-phenyl)-NH—, (2,4-diCl-phenyl)-NH—,

[1173] (2,5-diCl-phenyl)-NH—, (2,6-diCl-phenyl)-NH—,

[1174] (3,4-diCl-phenyl)-NH—, (3,5-diCl-phenyl)-NH—,

[1175] (2,3-diF-phenyl)-NH—, (2,4-diF-phenyl)-NH—,

[1176] (2,5-diF-phenyl)-NH—, (2,6-diF-phenyl)-NH—,

[1177] (3,4-diF-phenyl)-NH—, (3,5-diF-phenyl)-NH—,

[1178] (2,3-diCH₃-phenyl)-NH—, (2,4-diCH₃-phenyl)-NH—,

[1179] (2,5-diCH₃-phenyl)-NH—, (2,6-diCH₃-phenyl)-NH—,

[1180] (3,4-diCH₃-phenyl)-NH—, (3,5-diCH₃-phenyl)-NH—,

[1181] (2,3-diCF₃-phenyl)-NH—, (2,4-diCF₃-phenyl)-NH—,

[1182] (2,5-diCF₃-phenyl)-NH—, (2,6-diCF₃-phenyl)-NH—,

[1183] (3,4-diCF₃-phenyl)-NH—, (3,5-diCF₃-phenyl)-NH—,

[1184] (2,3-dioMe-phenyl)-NH—, (2,4-dioMe-phenyl)-NH—,

[1185] (2,5-dioMe-phenyl)-NH—, (2,6-diOMe-phenyl)-NH—,

[1186] (3,4-dioMe-phenyl)-NH—, (3,5-diOMe-phenyl)-NH—,

[1187] (2-F-3-Cl-phenyl)-NH—, (2-F-4-Cl-phenyl)-NH—,

[1188] (2-F-5-Cl-phenyl)-NH—, (2-F-6-Cl-phenyl)-NH—,

[1189] (2-F-3-CH₃-phenyl)-NH—, (2-F-4-CH₃ -phenyl)-NH—,

[1190] (2-F-5-CH₃-phenyl)-NH—, (2-F-6-CH₃-phenyl)-NH—,

[1191] (2-F-3-CF₃-phenyl)-NH—, (2-F-4-CF₃-phenyl)-NH—,

[1192] (2-F-5-CF₃-phenyl)-NH—, (2-F-6-CF₃-phenyl)-NH—,

[1193] (2-F-3-OMe-phenyl)-NH—, (2-F-4-OMe-phenyl)-NH—,

[1194] (2-F-5-OMe-phenyl)-NH—, (2-F-6-OMe-phenyl)-NH—,

[1195] (2-Cl-3-F-phenyl)-NH—, (2-Cl-4-F-phenyl)-NH—,

[1196] (2-Cl-5-F-phenyl)-NH—, (2-Cl-6-F-phenyl)-NH—,

[1197] (2-Cl-3-CH₃-phenyl)-NH—, (2-Cl-4-CH₃-phenyl)-NH—,

[1198] (2-Cl-5-CH₃-phenyl)-NH—, (2-Cl-6-CH₃-phenyl)-NH—,

[1199] (2-Cl-3-CF₃-phenyl)-NH—, (2-Cl-4-CF₃-phenyl)-NH—,

[1200] (2-Cl-5-CF₃-phenyl)-NH—, (2-Cl-6-CF₃-phenyl)-NH—,

[1201] (2-Cl-3-OMe-phenyl)-NH—, (2-Cl-4-OMe-phenyl)-NH—,

[1202] (2-Cl-5-OMe-phenyl)-NH—, (2-Cl-6-OMe-phenyl)-NH—,

[1203] (2-CH₃-3-F-phenyl)-NH—, (2-CH₃-4-F-phenyl)-NH—,

[1204] (2-CH₃-5-F-phenyl)-NH—, (2-CH₃-6-F-phenyl)-NH—,

[1205] (2-CH₃-3-Cl-phenyl)-NH—, (2-CH₃-4-Cl-phenyl)-NH—,

[1206] (2-CH₃-5-Cl-phenyl)-NH—, (2-CH₃-6-Cl-phenyl)-NH—,

[1207] (2-CH₃-3-CF₃-phenyl)-NH—, (2-CH₃-4-CF₃-phenyl)-NH—,

[1208] (2-CH₃-5-CF₃-phenyl)-NH—, (2-CH₃-6-CF₃-phenyl)-NH—,

[1209] (2-CH₃-3-OMe-phenyl)-NH—, (2-CH₃-4-OMe-phenyl)-NH—,

[1210] (2-CH₃-5-OMe-phenyl)-NH—, (2-CH₃-6-OMe-phenyl)-NH—,

[1211] (2-CF₃-3-F-phenyl)-NH—, (2-CF₃-4-F-phenyl)-NH—,

[1212] (2-CF₃-5-F-phenyl)-NH—, (2-CF₃-6-F-phenyl)-NH—,

[1213] (2-CF₃-3-Cl-phenyl)-NH—, (2-CF₃-4-Cl-phenyl)-NH—,

[1214] (2-CF₃-5-Cl-phenyl)-NH—, (2-CF₃-6-Cl-phenyl)-NH—,

[1215] (2-CF₃-3-CH₃-phenyl)-NH—, (2-CF₃-4-CH₃-phenyl)-NH—,

[1216] (2-CH₃-5-CF₃-phenyl)-NH—, (2-CF₃-6-CH₃-phenyl)-NH—,

[1217] (2-CF₃-3-OMe-phenyl)-NH—, (2-CF₃-4-OMe-phenyl)-N—,

[1218] (2-CF₃-5-OMe-phenyl)-NH—, (2-CF₃-6-OMe-phenyl)-NH—,

[1219] (2-OMe-3-F-phenyl)-NH—, (2-OMe-4-F-phenyl)-NH—,

[1220] (2-OMe-5-F-phenyl)-NH—, (2-OMe-6-F-phenyl)-NH—,

[1221] (2-OMe-3-Cl-phenyl)-NH—, (2-OMe-4-Cl-phenyl)-NH—,

[1222] (2-OMe-5-Cl-phenyl)-NH—, (2-OMe-6-Cl-phenyl)-NH—,

[1223] (2-OMe-3-CH₃-phenyl)-NH—, (2-OMe-4-CH₃-phenyl)-NH—,

[1224] (2-OMe-5-CH₃-phenyl)-NH—, (2-OMe-6-CH₃-phenyl)-NH—,

[1225] (2-OMe-3-CF₃-phenyl)-NH—, (2-OMe-4-CF₃-phenyl)-NH—,

[1226] (2-OMe-5-CF₃-phenyl)-NH—, (2-OMe-6-CF₃-phenyl)-NH—

[1227] (3-CF₃-4-Cl-phenyl)-NH—, (3-CF₃-4-C(O)CH₃-phenyl)-NH—,

[1228] (2,3,5-triCl-phenyl)-NH—, (3-CH₃-4-CO₂Me-phenyl)-NH—, and

[1229] (3-CHO-4-OMe-phenyl)-NH—.

[1230] [11] In another embodiment, the present invention provides anovel compound of Formula (I):

[1231] or a stereoisomer or a pharmaceutically acceptable salt formthereof, wherein:

[1232] R¹ is selected from

[1233] C₁₋₆ alkyl substituted with Z,

[1234] C₂₋₆ alkenyl substituted with Z,

[1235] C₂₋₆ alkynyl substituted with Z,

[1236] C₃₋₆ cycloalkyl substituted with Z,

[1237] aryl substituted with Z,

[1238] 5-6 membered heterocyclic ring system containing at least oneheteroatom selected from the group consisting of N, O, and S, saidheterocyclic ring system substituted with Z;

[1239] C₁₋₆ alkyl substituted with 0-2 R²,

[1240] C₂₋₆ alkenyl substituted with 0-2 R²,

[1241] C₂₋₆ alkynyl substituted with 0-2 R²,

[1242] aryl substituted with 0-2 R², and

[1243] 5-6 membered heterocyclic ring system containing at least oneheteroatom selected from the group consisting of N, O, and S, saidheterocyclic ring system substituted with 0-2 R²;

[1244] Z is selected from H,

[1245] —CH(OH)R²,

[1246] —C(ethylenedioxy)R²,

[1247] —OR²,

[1248] —SR²,

[1249] —NR²R³,

[1250] —C(O) R²,

[1251] —C(O)NR²R³,

[1252] —NR³C(O)R²,

[1253] —C(O)OR²,

[1254] —OC(O)R²,

[1255] —CH(═NR⁴)NR²R³,

[1256] —NHC(═NR⁴)NR²R³,

[1257] —S(O) R²,

[1258] —S(O)₂R²,

[1259] —S(O)₂NR²R³, and —NR³S(O)₂R²;

[1260] R², at each occurrence, is independently selected from

[1261] C₁₋₄ alkyl,

[1262] C₂₋₄ alkenyl,

[1263] C₂₋₄ alkynyl,

[1264] C₃₋₆ cycloalkyl,

[1265] aryl substituted with 0-5 R⁴²;

[1266] C₃₋₁₀ carbocyclic residue substituted with 0-3 R⁴¹, and

[1267] 5-10 membered heterocyclic ring system containing from 1-4heteroatoms selected from the group consisting of N, O, and Ssubstituted with 0-3 R⁴¹;

[1268] R³, at each occurrence, is independently selected from H, C₁₋₄alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, and C₁₋₄ alkoxy;

[1269] alternatively, R² and R³ join to form a 5- or 6-membered ringoptionally substituted with —O— or —N(R⁴)—;

[1270] R⁴, at each occurrence, is independently selected from H, methyl,ethyl, propyl, and butyl;

[1271] R^(4a) is H or C₁₋₄ alkyl;

[1272] R^(4b) is H;

[1273] alternatively, R^(4a) and R^(4b) are taken together to form ═O or═S;

[1274] R⁵ is H or C₁₋₄ alkyl;

[1275] R⁶ is H or C₁₋₄ alkyl;

[1276] alternatively, R⁵ and R⁶ are taken together to form a fusedheterocyclic ring of formula:

[1277] wherein:

[1278] X is a bond, —CH₂—, —O—, —S—, —S(═O)—,13 S(═O)₂—,

[1279] —NR¹⁰—, —CH₂CH₂—, —OCH₂—, —SCH₂—, —CH₂O—, —CH₂S—,

[1280] —CH₂NR¹⁰—, —NR¹⁰OCH₂—, —NHC(═O)—, or —C(═O)NH—; and

[1281] n is 1 or 2;

[1282] R⁷, R⁸, and R⁹, at each occurrence, are independently selectedfrom

[1283] H, halo, —CF₃, —OCF₃, —OH, —CN, —NO₂, —NR⁴⁶R⁴⁷,

[1284] C₁₋₈ alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, C₁₋₄ haloalkyl, C₁₋₈alkoxy, (C₁₋₄ haloalkyl)oxy,

[1285] C₁₋₄ alkyl substituted with 0-2 R¹¹,

[1286] C₃₋₁₀ carbocyclic residue substituted with 0-3 R³³,

[1287] aryl substituted with 0-5 R³³,

[1288] 5-10 membered heterocycl ic ri ng system containing from 1-4heteroatoms selected from the group consisting of N, O, and Ssubstituted with 0-3 R³¹;

[1289] OR¹², SR¹², NR¹²R¹³, C(O)H, C(O)R¹², C(O)NR¹²R¹³,

[1290] NR¹⁴C(O)R¹², C(O)OR¹², OC(O)R¹², OC(O)OR¹²,

[1291] CH(═NR¹⁴)NR¹²R¹³, NHC(═NR¹⁴)NR¹²R¹³, S(O)R¹², S(O)₂R¹²,

[1292] S(O)NR¹²R¹³, S(O)₂NR¹²R¹³, NR¹⁴S(O)R¹², NR¹⁴S(O)₂R¹²,

[1293] NR¹²C(O)R¹⁵, NR¹²C(O)OR¹⁵, NR¹²S(O)₂R¹⁵, and

[1294] NR¹²C(O)NHR¹⁵;

[1295] R¹⁰ is selected from H, C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl,and C₁₋₄ alkoxy;

[1296] R¹¹ is selected from

[1297] H, halo, —CF₃, —CN, —NO₂,

[1298] C₁₋₈ alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, C₁₋₄ haloalkyl, C₁₋₈alkoxy, C₃₋₁₀ cycloalkyl,

[1299] C₃₋₁₀ carbocyclic reside substituted with 0-3 R³³,

[1300] aryl substituted with 0-5 R³³,

[1301] 5-10 membered heterocyclic ring system containing from 1-4heteroatoms selected from the group consisting of N, O, and Ssubstituted with 0-3 R³¹;

[1302] OR¹², SR¹², NR¹²R¹³, C(O)H, C(O)R¹², C(O)NR¹²R¹³, NR¹⁴C(O)R¹²,C(O)OR¹², OC(O)R¹², OC(O)OR¹², CH(═NR¹⁴)NR¹²R¹³, NHC(═NR¹⁴)NR¹²R¹³,S(O)R¹², S(O)₂R¹², S(O)NR¹²R¹³, S(O)₂NR¹²R¹³, NR¹⁴S(O)R¹², andNR¹⁴S(O)₂R¹²;

[1303] R¹², at each occurrence, is independently selected from

[1304] C₁₋₄ alkyl,

[1305] C₂₋₄ alkenyl,

[1306] C₂₋₄ alkynyl,

[1307] C₃₋₆ cycloalkyl,

[1308] aryl substituted with 0-5 R³³;

[1309] C₃₋₁₀ carbocyclic residue substituted with 0-3 R³³, and

[1310] 5-10 membered heterocyclic ring system containing from 1-4heteroatoms selected from the group consisting of N, O, and Ssubstituted with 0-3 R³¹;

[1311] R¹³, at each occurrence, is independently selected from H, C₁₋₄alkyl, C₂₋₄ alkenyl, and C₂₋₄ alkynyl;

[1312] alternatively, R¹² and R¹³ join to form a 5- or 6-membered ringoptionally substituted with —O— or —N(R¹⁴)—;

[1313] R¹⁴, at each occurrence, is independently selected from H andC₁₋₄ alkyl;

[1314] R³¹, at each occurrence, is independently selected from

[1315] H, OH, halo, CF₃, SO₂R⁴⁵, NR⁴⁶R⁴⁷, methyl, ethyl, and propyl;

[1316] R³³, at each occurrence, is independently selected from

[1317] H, OH, halo, CN, NO₂, CF₃, SO₂R⁴⁵, NR⁴⁶R⁴⁷,

[1318] C₁₋₃ alkyl, C₂₋₃ alkenyl, C₂₋₃ alkynyl, C₃₋₅ cycloalkyl, C₁₋₃haloalkyl, C₁₋₃ haloalkyl-oxy-, C₁₋₃ alkyloxy-, C₁₋₃ alkylthio-, C₁₋₃alkyl-C(═O)—, and C₁₋₃ alkyl-C(═O)NH—;

[1319] R⁴¹, at each occurrence, is independently selected from

[1320] H, CF₃, halo, OH, CO₂H, SO₂R⁴⁵, NR⁴⁶R⁴⁷, NO₂, CN, ═O,

[1321] C₂₋₈ alkenyl, C₂₋₈ alkynyl, C₁₋₄ alkoxy, C₁₋₄ haloalkyl

[1322] C₁₋₄ alkyl substituted with 0-1 R⁴³,

[1323] aryl substituted with 0-3 R⁴², and

[1324] 5-10 membered heterocyclic ring system containing from 1-4heteroatoms selected from the group consisting of N, O, and Ssubstituted with 0-3 R⁴⁴;

[1325] R⁴², at each occurrence, is independently selected from

[1326] H, CF₃, halo, OH, CO₂H, SO₂R⁴⁵, SR⁴⁵, NR⁴⁶R⁴⁷, OR⁴⁸, NO₂, CN,CH(═NH)NH₂, NHC(═NH)NH₂,

[1327] C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₄ alkoxy, C₁₋₄ haloalkyl, C₃₋₆cycloalkyl,

[1328] C₁₋₄ alkyl substituted with 0-1 R⁴³,

[1329] aryl substituted with 0-3 R⁴⁴, and

[1330] 5-10 membered heterocyclic ring system containing from 1-4heteroatoms selected from the group consisting of N, O, and Ssubstituted with 0-3 R⁴⁴.

[1331] R⁴³ is C₃₋₆ cycloalkyl or aryl substituted with 0-3 R⁴⁴;

[1332] R⁴⁴, at each occurrence, is independently selected from H, halo,—OH, NR⁴⁶R⁴⁷, CO₂H, SO₂R⁴⁵, —CF₃, —OCF₃, —CN, —NO₂, C₁₋₄ alkyl, and C₁₋₄alkoxy;

[1333] R⁴⁵ is C₁₋₄ alkyl;

[1334] R⁴⁶, at each occurrence, is independently selected from H andC₁₋₄ alkyl;

[1335] R⁴⁷, at each occurrence, is independently selected from H, C₁₋₄alkyl, —C(═O)NH(C₁₋₄ alkyl), —SO₂(C₁₋₄ alkyl), —SO₂(phenyl),—C(═O)O(C₁₋₄ alkyl), —C(═O) (C₁₋₄ alkyl), and —C(═O)H; and

[1336] R⁴⁸, at each occurrence, is independently selected from H, C₁₋₄alkyl, —C(═O)NH(C₁₋₄ alkyl), —C(═O)O(C₁₋₄ alkyl), —C(═O) ( C₁₋₄ alkyl),and —C(═O)H;

[1337] provided when R⁵ is H or C₁₋₄ alkyl; and R⁶ is H or C₁₋₄ alkyl;then R¹ is not C₁₋₆ alkyl.

[1338] [12] In another embodiment, the present invention provides anovel compound of Formula (I):

[1339] R1 is selected from

[1340] ethyl substituted with Z,

[1341] propyl substituted with Z,

[1342] butyl substituted with Z,

[1343] propenyl substituted with Z,

[1344] butenyl substituted with Z,

[1345] ethyl substituted with R²,

[1346] propyl substituted with R²,

[1347] butyl substituted with R²,

[1348] propenyl substituted with R², and

[1349] butenyl substituted with R²;

[1350] Z is selected from H,

[1351] —CH(OH)R²,

[1352] —OR²,

[1353] —SR²,

[1354] —NR²R³,

[1355] —C(O)R²,

[1356] —C(O)NR²R³,

[1357] —NR³C(O)R²,

[1358] —C(O)OR²,

[1359] —S(O)R²,

[1360] —S(O)₂R²,

[1361] —S(O)₂NR²R³, and —NR³S(O)₂R²;

[1362] R², at each occurrence, is independently selected from

[1363] phenyl substituted with 0-3 R⁴²;

[1364] naphthyl substituted with 0-3 R⁴²;

[1365] cyclopropyl substituted with 0-3 R⁴¹;

[1366] cyclobutyl substituted with 0-3 R⁴¹;

[1367] cyclopentyl substituted with 0-3 R⁴¹;

[1368] cyclohexyl substituted with 0-3 R⁴¹;

[1369] pyridyl substituted with 0-3 R⁴¹;

[1370] indolyl substituted with 0-3 R⁴¹;

[1371] indolinyl substituted with 0-3 R⁴¹;

[1372] benzimidazolyl substituted with 0-3 R⁴¹;

[1373] benzotriazolyl substituted with 0-3 R⁴¹;

[1374] benzothienyl substituted with 0-3 R⁴¹;

[1375] benzofuranyl substituted with 0-3 R⁴¹;

[1376] phthalimid-1-yl substituted with 0-3 R⁴¹;

[1377] inden-2-yl substituted with 0-3 R⁴¹;

[1378] 2,3-dihydro-1H-inden-2-yl substituted with 0-3 R⁴¹;

[1379] indazolyl substituted with 0-3 R⁴¹;

[1380] tetrahydroquinolinyl substituted with 0-3 R⁴¹; and

[1381] tetrahydro-isoquinolinyl substituted with 0-3 R⁴¹;

[1382] R³, at each occurrence, is independently selected from H, methyl,and ethyl;

[1383] R^(4a) is H or C₁₋₄ alkyl;

[1384] R^(4b) is H;

[1385] alternatively, R^(4a) and R^(4b) are taken together to form ═O;

[1386] R⁵ is H or C₁₋₄ alkyl;

[1387] R⁶ is H or C₁₋₄ alkyl;

[1388] alternatively, R⁵ and R⁶ are taken together to form a fusedheterocyclic ring of formula:

[1389] wherein:

[1390] X is —CH₂—, —O—, or —S—; and

[1391] n is 1;

[1392] R⁷, R⁸, and R⁹, at each occurrence, are independently selectedfrom H, F, Cl, methyl, ethyl, methoxy, —CF₃, and —OCF₃;

[1393] R⁴¹, at each occurrence, is independently selected from H, F, Cl,Br, OH, CF₃, NO₂, CN, ═O, methyl, ethyl, propyl, butyl, methoxy, andethoxy;

[1394] R⁴², at each occurrence, is independently selected from H, F, Cl,Br, OH, CF₃, SO₂R⁴⁵, SR⁴⁵, NR⁴⁶R⁴⁷, OR⁴⁸, NO₂, CN, ═O, methyl, ethyl,propyl, butyl, methoxy, and ethoxy;

[1395] R⁴⁵ is methyl, ethyl, propyl, or butyl;

[1396] R⁴⁶, at each occurrence, is independently selected from H,methyl, ethyl, propyl, and butyl;

[1397] R⁴⁷, at each occurrence, is independently selected from H,methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, —C(═O)NH(methyl),—C(═O)NH(ethyl), —SO₂(methyl), —SO₂(ethyl), —SO₂(phenyl),—C(═O)O(methyl), —C(═O)O(ethyl), —C(═O)(methyl), —C(═O)(ethyl), and—C(═O)H;

[1398] R⁴⁸, at each occurrence, is independently selected from H,methyl, ethyl, n-propyl, i-propyl, —C(═O)NH(methyl), —C(═O)NH(ethyl),—C(═O)O(methyl), —C(═O)O(ethyl), —C(═O) (methyl), —C(═O) (ethyl), and—C(═O)H.

[1399] [13] In another embodiment, the present invention provides anovel compound of Formula (I):

[1400] R¹ is selected from

[1401] —(CH₂)₃C(═O) (4-fluoro-phenyl),

[1402] —(CH₂)₃C(═O) (4-bromo-phenyl),

[1403] —(CH₂)₃C(═O) (4-methyl-phenyl),

[1404] —(CH₂)₃C(═O) (4-methoxy-phenyl),

[1405] —(CH₂)₃C(═O) (4-(3,4-dichloro-phenyl)phenyl),

[1406] —(CH₂)₃C(═O) (3-methyl-4-fluoro-phenyl),

[1407] —(CH₂)₃C(═O) (2,3-dimethoxy-phenyl),

[1408] —(CH₂)₃C(═O) (phenyl),

[1409] —(CH₂)₃C(═O) (4-chloro-phenyl),

[1410] —(CH₂)₃C(═O) (3-methyl-phenyl),

[1411] —(CH₂)₃C(═O) (4-t-butyl-phenyl),

[1412] —(CH₂)₃C(═O) (3,4-difluoro-phenyl),

[1413] —(CH₂)₃C(═O) (2-methoxy-5-fluoro-phenyl),

[1414] —(CH₂)₃C(═O) (4-fluoro-1-naphthyl),

[1415] —(CH₂)₃C(═O) (benzyl),

[1416] —(CH₂)₃C(═O) (4-pyridyl),

[1417] —(CH₂)₃C(═O) (3-pyridyl),

[1418] —(CH₂)₃CH (OH) (4-fluoro-phenyl),

[1419] —(CH₂)₃CH (OH) (4-pyridyl),

[1420] —(CH₂)₃CH (OH) (2,3-dimethoxy-phenyl),

[1421] —(CH₂)₃S(3-fluoro-phenyl),

[1422] —(CH₂)₃S(4-fluoro-phenyl),

[1423] —(CH₂)₃S(═O) (4-fluoro-phenyl),

[1424] —(CH₂)₃SO₂(3-fluoro-phenyl) ,

[1425] —(CH₂)₃SO₂(4-fluoro-phenyl),

[1426] —(CH₂)₃O(4-fluoro-phenyl),

[1427] —(CH₂)₃O(phenyl),

[1428] —(CH₂)₃O(3-pyridyl),

[1429] —(CH₂)₃O(4-pyridyl),

[1430] —(CH₂)₃O(2-NH₂-phenyl),

[1431] —(CH₂)₃O(2-NH₂-5-F-phenyl),

[1432] —(CH₂)₃O(2-NH₂-4-F-phenyl)

[1433] —(CH₂)₃O(2-NH₂-3-F-phenyl)

[1434] —(CH₂)₃O(2-NH₂-4-Cl-phenyl),

[1435] —(CH₂)₃O(2-NH₂-4-OH-phenyl),

[1436] —(CH₂)₃O(2-NH₂-4-Br-phenyl),

[1437] —(CH₂)₃O(2-NHC(═)Me-4-F-phenyl),

[1438] —(CH₂)₃O(2-NHC (═O) Me-phenyl),

[1439] —(CH₂)₃NH(4-fluoro-phenyl),

[1440] —(CH₂)₃N(methyl) (4-fluoro-phenyl),

[1441] —(CH₂)₃CO₂(ethyl),

[1442] —(CH₂)₃C(═O)N(methyl) (methoxy),

[1443] —(CH₂)₃C(═O)NH(4-fluoro-phenyl) ,

[1444] —(CH₂)₂NHC(═O) (phenyl),

[1445] —(CH₂)₂NMeC(═O) (phenyl),

[1446] —(CH₂)₂NHC(═O) (2-fluoro-phenyl),

[1447] —(CH₂)₂NMeC(═O) (2-fluoro-phenyl),

[1448] —(CH₂)₂NHC(═O) (4-fluoro-phenyl),

[1449] —(CH₂)₂NMeC(═O) (4-fluoro-phenyl),

[1450] —(CH₂)₂NHC(═O) (2,4-difluoro-phenyl),

[1451] —(CH₂)₂NMeC(═O) (2,4-difluoro-phenyl),

[1452] —(CH₂)₃(3-indolyl),

[1453] —(CH₂)₃(1-methyl-3-indolyl),

[1454] —(CH₂)₃(1-indolyl),

[1455] —(CH₂)₃(1-indolinyl),

[1456] —(CH₂)₃(1-benzimidazolyl),

[1457] —(CH₂)₃(1H-1,2,3-benzotriazol-1-yl) ,

[1458] —(CH₂)₃(1H-1,2,3-benzotriazol-2-yl) ,

[1459] —(CH₂)₂(1H-1,2,3-benzotriazol-1-yl),

[1460] —(CH₂)₂(1H-1,2,3-benzotriazol-2-yl),

[1461] —(CH₂)₃(3,4 dihydro-1(2H)-quinolinyl),

[1462] —(CH₂)₂C(═O) (4-fluoro-phenyl),

[1463] —(CH₂)₂C(═O)NH(4-fluoro-phenyl) ,

[1464] —CH₂CH₂(3-indolyl),

[1465] —CH₂CH₂(1-phthalimidyl),

[1466] —(CH₂)₄C(═O)N(methyl) (methoxy),

[1467] —(CH₂)₄CO₂(ethyl),

[1468] —(CH₂)₄C(═O) (phenyl),

[1469] —(CH₂)₄ (cyclohexyl),

[1470] —(CH₂)₃CH(phenyl)₂,

[1471] —CH₂CH₂CH═C(phenyl)₂,

[1472] —CH₂CH₂CH═CMe(4- F-phenyl),

[1473] —(CH₂)₃CH(4-fluoro-phenyl)₂,

[1474] —CH₂CH₂CH═C(4-fluoro-phenyl)₂,

[1475] —(CH₂)₂(2,3-dihydro-1H-inden-2-yl),

[1476] —(CH₂)₃C(═O) (2-NH₂-phenyl),

[1477] —(CH₂)₃C(═O)(2-NH₂-5-F-phenyl),

[1478] —(CH₂)₃C(═O) (2-NH₂-4-F-phenyl),

[1479] —(CH₂)₃C(═O) (2-NH₂-3-F-phenyl),

[1480] —(CH₂)₃C(═O) (2-NH₂-4-Cl-phenyl),

[1481] —(CH₂)₃C(═O) (2-NH₂-4-OH-phenyl),

[1482] —(CH₂)₃C(═O) (2-NH₂-4-Br-phenyl),

[1483] —(CH₂)₃(1H-indazol-3-yl),

[1484] —(CH₂)₃(5-F-1H-indazol-3-yl) ,

[1485] —(CH₂)₃(7-F-1H-indazol-3-yl),

[1486] —(CH₂)₃(6-Cl-1H-indazol-3-yl),

[1487] —(CH₂)₃(6 -Br-1H-indazol-3-yl)

[1488] —(CH₂)₃C(═O) (2-NHMe-phenyl),

[1489] —(CH₂)₃(1-benzothien-3-yl),

[1490] —(CH₂)₃(6-F-1H-indol-1-yl),

[1491] —(CH₂)₃(5-F-1H-indol-1-yl),

[1492] —(CH₂)₃(6-F-2,3-dihydro-1H-indol-1-yl),

[1493] —(CH₂)₃(5-F-2,3-dihydro-1H-indol-1-yl),

[1494] —(CH₂)₃(6-F-1H-indol-3-yl),

[1495] —(CH₂)₃(5-F-1H-indol-3-yl),

[1496] —(CH₂)₃(5-F-1H-indol-3-yl),

[1497] —(CH₂)₃(9H-purin-9-yl),

[1498] —(CH₂)₃(7H-purin-7-yl),

[1499] —(CH₂)₃(6-F-1H-indazol-3-yl),

[1500] —(CH₂)₃C(═O) (2-NHSO₂Me-4-F-phenyl),

[1501] —(CH₂)₃C(═O) (2-NHC(═O)Me-4-F-phenyl),

[1502] —(CH₂)₃C(═O) (2-NHC(═O)Me-phenyl),

[1503] —(CH₂)₃C(═O) (2-NHCO₂Et-4-F-phenyl),

[1504] —(CH₂)₃C(═O) (2-NHC(═O)NHEt-4-F-phenyl),

[1505] —(CH₂)₃C(═O) (2-NHCHO-4-F-phenyl),

[1506] —(CH₂)₃C(═O) (2-OH-4-F-phenyl),

[1507] —(CH₂)₃C(═O) (2-MeS-4-F-phenyl),

[1508] —(CH₂)₃C(═O) (2-NHSO₂Me-4-F-phenyl),

[1509] —(CH₂)₂C(Me)CO₂Me,

[1510] —(CH₂)₂C(Me)CH(OH) (4-F-phenyl)₂,

[1511] —(CH₂)₂C(Me)CH(OH) (4-Cl-phenyl)₂,

[1512] —(CH₂)₂C(Me)C(═O) (4-F-phenyl),

[1513] —(CH₂)₂C(Me)C(═O) (2-MeO-4-F-phenyl),

[1514] —(CH₂)₂C(Me)C(═O) (3-Me-4-F-phenyl),

[1515] —(CH₂)₂C(Me)C(═O) (2-Me-phenyl),

[1516] —(CH₂)₂C(Me)C(═O)phenyl,

[1517] R^(4a) is H;

[1518] R^(4b) is H;

[1519] alternatively, R^(4a) and R^(4b) are taken together to form ═O;

[1520] R⁵ is H, methyl, ethyl, propyl, or butyl;

[1521] R⁶ is H, methyl, ethyl, propyl, or butyl;

[1522] alternatively, R⁵ and R6 are taken together to form a fusedheterocyclic ring of formula:

[1523] wherein:

[1524] X is —CH₂—, —O—, or —S—; and

[1525] n is 1;

[1526] R⁷, R⁸, and R⁹, at each occurrence, are independently selectedfrom

[1527] hydrogen, fluoro, chloro, bromo, cyano, methyl, ethyl,

[1528] propyl, isopropyl, butyl, t-butyl, nitro,

[1529] trifluoromethyl, methoxy, ethoxy, isopropoxy,

[1530] trifluoromethoxy, phenyl, benzyl,

[1531] HC(═O)—, methylC(═O)—, ethylC(═O)—, propylC(═O)—,

[1532] isopropylC(═O)—, n-butylC(═O)—, isobutylC(═O)—,

[1533] secbutylC(═O)—, tertbutylC(═O)—, phenylC(═O)—,

[1534] methylC(═O)NH—, ethylC(═O)NH—, propylC(═O)NH—,

[1535] isopropylC(═O)NH—, n-butylC(═O)NH—, isobutylC(═O)NH—,

[1536] secbutylC(═O)NH—, tertbutylC(═O)NH—, phenylC(═O)NH—,

[1537] methylamino-, ethylamino-, propylamino-, isopropylamino-,

[1538] n-butylamino-, isobutylamino-, secbutylamino-,

[1539] tertbutylamino-, phenylamino-,

[1540] provided that two of substituents R⁷, R⁸, and R⁹, areindependently selected from hydrogen, fluoro, chloro, bromo, cyano,methyl, ethyl, propyl, isopropyl, butyl, t-butyl, nitro,trifluoromethyl, methoxy, ethoxy, isopropoxy, and trifluoromethoxy.

[1541] In an even further more preferred embodiment of the presentinvention, are compounds of Formula (I) selected from disclosed Examples1-8.

[1542] In a second embodiment, the present invention provides apharmaceutical composition comprising a compound of Formula (I) and apharmaceutically acceptable carrier.

[1543] In a third embodiment, the present invention provides a methodfor the treatment a central nervous system disorder comprisingadministering to a host in need of such treatment a therapeuticallyeffective amount of a compound of Formula (I), or a pharmaceuticallyacceptable salt thereof, wherein the compound is a 5HT2a antagonist or a5HT2c agonist.

[1544] In a preferred embodiment the compound is a 5HT2a antagonist.

[1545] In another preferred embodiment the compound isa 5HT2c agonist.

[1546] In a more preferred embodiment the present invention provides amethod for the treatment central nervous system disorders includingobesity, anxiety, depression, psychosis, schizophrenia, sleep disorders,sexual disorders, migraine, conditions associated with cephalic pain,social phobias, and gastrointestinal disorders such as dysfunction ofthe gastrointestinal tract motility comprising administering to a hostin need of such treatment a therapeutically effective amount of acompound of Formula (I).

[1547] In a further preferred embodiment the central nervous systemdisorder comprises obesity.

[1548] In another further preferred embodiment the central nervoussystem disorder comprises schizophrenia.

[1549] In another further preferred embodiment the central nervoussystem disorder comprises depression.

[1550] In another further preferred embodiment the central nervoussystem disorder comprises anxiety.

[1551] In a fourth embodiment the present invention provides novelcompounds of Formula (I) or pharmaceutically acceptable salt formsthereof for use in therapy.

[1552] In a fifth embodiment the present invention provides the use ofnovel compounds of Formula (I) or pharmaceutically acceptable salt formsthereof for the manufacture of a medicament for the treatment of centralnervous system disorders including obesity, anxiety, depression,psychosis, schizophrenia, sleep disorders, sexual disorders, migraine,conditions associated with cephalic pain, social phobias, andgastrointestinal disorders.

DEFINITIONS

[1553] The compounds herein described may have asymmetric centers.Compounds of the present invention containing an asymmetricallysubstituted atom may be isolated in optically active or racemic forms.It is well known in the art how to prepare optically active forms, suchas by resolution of racemic forms or by synthesis from optically activestarting materials. Many geometric isomers of olefins, C═N double bonds,and the like can also be present in the compounds described herein, andall such stable isomers are contemplated in the present invention. Cisand trans geometric isomers of the compounds of the present inventionare described and may be isolated as a mixture of isomers or asseparated isomeric forms. All chiral, diastereomeric, racemic forms andall geometric isomeric forms of a structure are intended, unless thespecific stereochemistry or isomeric form is specifically indicated.

[1554] The term “substituted,” as used herein, means that any one ormore hydrogens on the designated atom is replaced with a selection fromthe indicated group, provided that the designated atom's normal valencyis not exceeded, and that the substitution results in a stable compound.When a substituent is keto (i.e., ═O), then 2 hydrogens on the atom arereplaced.

[1555] When any variable (e.g. R², R¹¹, R³³, R⁴¹, R⁴² etc.) occurs morethan one time in any constituent or formula for a compound, itsdefinition at each occurrence is independent of its definition at everyother occurrence. Thus, for example, if a group is shown to besubstituted with 0-2 R², then said group may optionally be substitutedwith up to two R² groups and R² at each occurrence is selectedindependently from the definition of R². Also, combinations ofsubstituents and/or variables are permissible only if such combinationsresult in stable compounds.

[1556] When a bond to a substituent is shown to cross a bond connectingtwo atoms in a ring, then such substituent may be bonded to any atom onthe ring. When a substituent is listed without indicating the atom viawhich such substituent is bonded to the rest of the compound of a givenformula, then such substituent may be bonded via any atom in suchsubstituent. Combinations of substituents and/or variables arepermissible only if such combinations result in stable compounds.

[1557] As used herein, “alkyl” or “alkylene” is intended to include bothbranched and straight-chain saturated aliphatic hydrocarbon groupshaving the specified number of carbon atoms; for example, “C₁-C₆ alkyl”or “C₁₋₆ alkyl” denotes alkyl having 1 to 6 carbon atoms. Examples ofalkyl include, but are not limited to, methyl, ethyl, n-propyl,i-propyl, n-butyl, i-butyl, sec-butyl, t-butyl, n-pentyl, n-hexyl,2-methylbutyl, 2-methylpentyl, 2-ethylbutyl, 3-methylpentyl, and4-methylpentyl.

[1558] “Alkenyl” or “alkenylene” is intended to include hydrocarbonchains of either a straight or branched configuration having thespecified number of carbon atoms, for example “C₂₋₆ alkenyl”, and one ormore unsaturated carbon-carbon bonds which may occur in any stable pointalong the chain. Examples of alkenyl include, but are not limited to,ethenyl, 1-propenyl, 2-propenyl, 2-butenyl, 3-butenyl, 2-pentenyl, 3,pentenyl, 4-pentenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl,2-methyl-2-propenyl, 4-methyl-3-pentenyl, and the like.

[1559] “Alkynyl” or “alkynylene” is intended to include hydrocarbonchains of either a straight or branched configuration, having thespecified number of carbon atoms, for example “C₂₋₆ alkynyl”, and one ormore carbon-carbon triple bonds which may occur in any stable pointalong the chain, such as ethynyl, propynyl, butynyl, pentynyl, hexynyland the like.

[1560] “Cycloalkyl” is intended to include saturated ring groups, havingthe specified number of carbon atoms. For example, “C₃-C₆ cycloalkyl”denotes such as cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.

[1561] “Alkoxy” or “alkyloxy” represents an alkyl group as defined abovewith the indicated number of carbon atoms attached through an oxygenbridge. Examples of alkoxy include, but are not limited to, methoxy,ethoxy, n-propoxy, i-propoxy, n-butoxy, s-butoxy, t-butoxy, n-pentoxy,and s-pentoxy. Similarly, “alkylthio” is represents an alkyl group asdefined above with the indicated number of carbon atoms attached througha sulpher bridge.

[1562] “Halo” or “halogen” as used herein refers to fluoro, chloro,bromo, and iodo; and “counterion” is used to represent a small,negatively charged species such as chloride, bromide, hydroxide,acetate, sulfate, and the like.

[1563] “Haloalkyl” is intended to include both branched andstraight-chain saturated aliphatic hydrocarbon groups having thespecified number of carbon atoms, substituted with 1 or more halogen(for example —CvFw where v=1 to 3 and w=1 to (2v+1)). Examples ofhaloalkyl include, but are not limited to, trifluoromethyl,trichloromethyl, pentafluoroethyl, pentachloroethyl,2,2,2-trifluoroethyl, heptafluoropropyl, and heptachloropropyl.

[1564] As used herein, “carbocycle” is intended to mean any stable 3- to7-membered monocyclic or bicyclic or 7- to 13-membered bicyclic ortricyclic, any of which may be saturated, partially unsaturated, oraromatic. Examples of such carbocycles include, but are not limited to,cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl,adamantyl, cyclooctyl, [3.3.0]bicyclooctane, [4.3.0]bicyclononane,[4.4.0]bicyclodecane (decalin), [2.2.2]bicyclooctane, fluorenyl, phenyl,naphthyl, indanyl, adamantyl, or tetrahydronaphthyl (tetralin).

[1565] As used herein, the term “heterocycle” or “heterocyclic ring” or“heterocyclic ring system” is intended to mean a stable 5- to 7-membered monocyclic or bicyclic or 7- to 14-membered bicyclicheterocyclic ring which is saturated partially unsaturated orunsaturated (aromatic), and which consists of carbon atoms and 1, 2, 3or 4 heteroatoms independently selected from the group consisting of N,O and S and including any bicyclic group in which any of theabove-defined heterocyclic rings is fused to a benzene ring. Thenitrogen and sulfur heteroatoms may optionally be oxidized. Theheterocyclic ring may be attached to its pendant group at any heteroatomor carbon atom which results in a stable structure. The heterocyclicrings described herein may be substituted on carbon or on a nitrogenatom if the resulting compound is stable. If specifically noted, anitrogen in the heterocycle may optionally be quaternized. It ispreferred that when the total number of S and O atoms in the heterocycleexceeds 1, then these heteroatoms are not adjacent to one another. It ispreferred that the total number of S and O atoms in the heterocycle isnot more than 1.

[1566] Examples of heterocycles include, but are not limited to,1H-indazole, 2-pyrrolidonyl, 2H,6H-1,5,2-dithiazinyl, 2H-pyrrolyl,3H-indolyl, 4-piperidonyl, 4aH-carbazole, 4H-quinolizinyl,6H-1,2,5-thiadiazinyl, acridinyl, azocinyl, benzimidazolyl,benzofuranyl, benzothiofuranyl, benzothiophenyl, benzoxazolyl,benzoxazolinyl, benzthiazolyl, benztriazolyl, benztetrazolyl,benzisoxazolyl, benzisothiazolyl, benzimidazalonyl, carbazolyl,4aH-carbazolyl, b-carbolinyl, chromanyl, chromenyl, cinnolinyl,decahydroquinolinyl, 2H,6H-1,5,2-dithiazinyl,dihydrofuro[2,3-b]tetrahydrofuran, furanyl, furazanyl, imidazolidinyl,imidazolinyl, imidazolyl, imidazolopyridinyl, 1H-indazolyl, indolenyl,indolinyl, indolizinyl, indolyl, isatinoyl, isobenzofuranyl,isochromanyl, isoindazolyl, isoindolinyl, isoindolyl, isoquinolinyl,isothiazolyl, isothiazolopyridinyl, isoxazolyl, isoxazolopyridinyl,morpholinyl, naphthyridinyl, octahydroisoquinolinyl, oxadiazolyl,1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl,1,3,4-oxadiazolyl, oxazolidinyl, oxazolyl, oxazolopyridinyl,oxazolidinylperimidinyl, oxindolyl, phenanthridinyl, phenanthrolinyl,phenarsazinyl, phenazinyl, phenothiazinyl, phenoxathiinyl, phenoxazinyl,phthalazinyl, piperazinyl, piperidinyl, pteridinyl, piperidonyl,4-piperidonyl, pteridinyl, purinyl, pyranyl, pyrazinyl, pyrazolidinyl,pyrazolinyl, pyrazolopyridinyl, pyrazolyl, pyridazinyl, pyridooxazole,pyridoimidazole, pyridothiazole, pyridinyl, pyridyl, pyrimidinyl,pyrrolidinyl, pyrrolinyl, pyrrolyl, quinazolinyl, quinolinyl,4H-quinolizinyl, quinoxalinyl, quinuclidinyl, carbolinyl,tetrahydrofuranyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl,6H-1,2,5-thiadiazinyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl,1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, thianthrenyl, thiazolyl,thiazolopyridinyl, thienyl, thienothiazolyl, thienooxazolyl,thienoimidazolyl, thiophenyl, triazinyl, 1,2,3-triazolyl,1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl, and xanthenyl.Preferred heterocycles include, but are not limited to, pyridinyl,furanyl, thienyl, pyrrolyl, pyrazolyl, pyrazinyl, piperazinyl,imidazolyl, indolyl, benzimidazolyl, 1H-indazolyl, oxazolidinyl,benzotriazolyl, benzisoxazolyl, benzoxazolyl, oxindolyl, benzoxazolinyl,benzthiazolyl, benzisothiazolyl, isatinoyl, isoxazolopyridinyl,isothiazolopyridinyl, thiazolopyridinyl, oxazolopyridinyl,imidazolopyridinyl, and pyrazolopyridinyl. Preferred 5 to 6 memberedheterocycles include, but are not limited to, pyridinyl, furanyl,thienyl, pyrrolyl, pyrazolyl, pyrazinyl, piperazinyl, imidazolyl, andoxazolidinyl. Also included are fused ring and spiro compoundscontaining, for example, the above heterocycles.

[1567] As used herein, the term “bicyclic heterocyclic ring system” isintended to mean a stable 9- to 10-membered bicyclic heterocyclic ringformed from the substituent NR¹²R¹³, which is partially unsaturated orunsaturated (aromatic), and which consists of carbon atoms, a nitrogenatom, and 1 or 2 additional heteroatoms independently selected from thegroup consisting of N, O and S. The additional nitrogen or sulfurheteroatoms may optionally be oxidized. The heterocyclic ring isattached to its pendant group by the nitrogen atom of the group NR¹²R¹³and for which results in a stable structure. The heterocyclic ringsdescribed herein may be substituted on carbon or on a nitrogen atom ifthe resulting compound is stable. If specifically noted, a nitrogen inthe heterocycle may optionally be quaternized. It is preferred that whenthe total number of S and O atoms in the heterocycle exceeds 1, thenthese heteroatoms are not adjacent to one another. It is preferred thatthe total number of S and O atoms in the heterocycle is not more than 1.The term “bicyclic heterocyclic ring system” is intended to be a subsetof the term “heterocyclic ring system”. Preferred examples of a 9- to10-membered bicyclic heterocyclic ring system are benzimidazolyl,benzimidazolinyl, benzoxazolinyl, dihydrobenzthiazolyl,dihydrodioxobenzthiazolyl, benzisoxazolinyl, 1H-indazolyl, indolyl,indolinyl, isoindolinyl, tetrahydro-isoquinolinyl,tetrahydro-quinolinyl, and benzotriazolyl.

[1568] Additionally, a subclass of preferred heterocycles areheterocycles which function as an isostere of a cyclic butnon-heterocyclic substitutent such as —CH₂—C(═O)-phenyl. Preferredexamples of such heterocycles include, but are not limited to,benzimidazolyl, benzofuranyl, benzothiophenyl, benzoxazolyl,benzthiazolyl, benzisoxazolyl, furanyl, imidazolinyl, 1H-indazolyl,indolinyl, isoindolinyl, isoquinolinyl, oxazolyl, piperidinyl,pyrazinyl, pyridinyl, pyrimidinyl, quinolinyl, thiazolyl, thiophenyl,and 1,2,3-triazolyl.

[1569] As used herein, the term “aryl”, or aromatic residue, is intendedto mean an aromatic moiety containing six to ten carbon atoms, such asphenyl, pyridinyl and naphthyl.

[1570] The phrase “pharmaceutically acceptable” is employed herein torefer to those compounds, materials, compositions, and/or dosage formswhich are, within the scope of sound medical judgment, suitable for usein contact with the tissues of human beings and animals withoutexcessive toxicity, irritation, allergic response, or other problem orcomplication, commensurate with a reasonable benefit/risk ratio.

[1571] As used herein, “pharmaceutically acceptable salts” refer toderivatives of the disclosed compounds wherein the parent compound ismodified by making acid or base salts thereof. Examples ofpharmaceutically acceptable salts include, but are not limited to,mineral or organic acid salts of basic residues such as amines; alkalior organic salts of acidic residues such as carboxylic acids; and thelike. The pharmaceutically acceptable salts include the conventionalnon-toxic salts or the quaternary ammonium salts of the parent compoundformed, for example, from non-toxic inorganic or organic acids. Forexample, such conventional non-toxic salts include those derived frominorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic,phosphoric, nitric and the like; and the salts prepared from organicacids such as acetic, propionic, succinic, glycolic, stearic, lactic,malic, tartaric, citric, ascorbic, pamoic, maleic, hydroxymaleic,phenylacetic, glutamic, benzoic, salicylic, sulfanilic,2-acetoxybenzoic, fumaric, toluenesulfonic, methanesulfonic, ethanedisulfonic, oxalic, isethionic, and the like.

[1572] The pharmaceutically acceptable salts of the present inventioncan be synthesized from the parent compound which contains a basic oracidic moiety by conventional chemical methods. Generally, such saltscan be prepared by reacting the free acid or base forms of thesecompounds with a stoichiometric amount of the appropriate base or acidin water or in an organic solvent, or in a mixture of the two;generally, nonaqueous media like ether, ethyl acetate, ethanol,isopropanol, or acetonitrile are preferred. Lists of suitable salts arefound in Remington's Pharmaceutical Sciences, 17th ed., Mack PublishingCompany, Easton, Pa., 1985, p. 1418, the disclosure of which is herebyincorporated by reference.

[1573] “Prodrugs” are intended to include any covalently bonded carrierswhich release the active parent drug according to formula (I) in vivowhen such prodrug is administered to a mammalian subject. Prodrugs of acompound of formula (I) are prepared by modifying functional groupspresent in the compound in such a way that the modifications arecleaved, either in routine manipulation or in vivo, to the parentcompound. Prodrugs include compounds of formula (I) wherein a hydroxy,amino, or sulfhydryl group is bonded to any group that, when the prodrugor compound of formula (I) is administered to a mammalian subject,cleaves to form a free hydroxyl, free amino, or free sulfhydryl group,respectively. Examples of prodrugs include, but are not limited to,acetate, formate and benzoate derivatives of alcohol and aminefunctional groups in the compounds of Formula (I), and the like. “Stablecompound” and “stable structure” are meant to indicate a compound thatis sufficiently robust to survive isolation to a useful degree of purityfrom a reaction mixture, and formulation into an efficacious therapeuticagent.

SYNTHESIS

[1574] Throughout the details of the invention, the followingabbreviations are used with the following meanings: Reagents: MCPBAm-chloroperoxybenzoic acid DIBAL dilsobutyl aluminum hydride Et₃Ntriethylamine TFA trifluoroacetic acid LAH lithium aluminum hydride NBSN-bromo succinimide Red-Al Sodium bis (2-methoxyethoxy) aluminum hydridePd₂dba₃ Tris (dibenzylideneacetone)dipalladium(0) ACE-Cl2-chloroethylchloroformate Solvents: THF tetrahydrofuran MeOH methanolEtOH ethanol EtOAc ethyl acetate HOAc acetic acid DMF dimethyl formamideDMSO dimethyl sulfoxide DME dimethoxyethane Et₂O diethylether iPrOHisopropanol Others: Ar aryl Ph phenyl Me methyl Et ethyl NMR nuclearmagnetic resonance MHz megahertz BOC tert -butoxycarbonyl CBZbenzyloxycarbonyl Bn benzyl Bu butyl Pr propyl cat. catalytic mLmilliliter nM nanometer ppm part per million mmol millimole mg milligramg gram kg kilogram TLC thin layer chromatography HPLC high pressureliquid chromatography rt room temperature aq. aqueous sat. saturated

[1575] The preparation of compounds of Formula (I) and (I-a) of thepresent invention may be carried out in a convergent or sequentialsynthetic manner. Detailed synthetic preparations of the compounds ofFormula (I) and (I-a) are shown in the following reaction schemes. Theskills required in preparation and purification of the compounds ofFormula (I) and (I-a) and the intermediates leading to these compoundsare known to those skilled in the art. Purification procedures include,but are not limited to, normal or reverse phase chromatography,crystallization, and distillation.

[1576] Preferred methods for the preparation of the compounds of thepresent invention include, but are not limited to, those shown in theschemes and examples below. The substitutions are as described anddefined in the claims. All references cited herein are herebyincorporated in their entirety herein by reference.

[1577] The novel compounds of this invention may be prepared using thereactions and techniques described in this section. The reactions areperformed in solvents appropriate to the reagents and materials employedand are suitable for the transformations being effected. Also, in thedescription of the synthetic methods described below, it is to beunderstood that all proposed reaction conditions, including choice ofsolvent, reaction atmosphere, reaction temperature, duration of theexperiment and workup procedures, are chosen to be the conditionsstandard for that reaction, which should be readily recognized by oneskilled in the art. It is understood by one skilled in the art oforganic synthesis that the functionality present on various portions ofthe molecule must be compatible with the reagents and reactionsproposed. Such restrictions to the substituents which are compatiblewith the reaction conditions will be readily apparent to one skilled inthe art and alternate methods must then be used.

[1578] Compounds of Formula (I) of this invention may be prepared asshown in Scheme 1. Thus, preparation of nitroaryl derivative (V) isaccomplished by treatment of the protected (R¹=CBz) piperidinecarboxylic acid (IV) and the nitrophenyl compound (III), where Z=Cl, Br,or F, with a suitable base, such as triethylamine, in an inert solvent,such as DMSO, at elevated temperatures (60-150° C.) Reduction of thenitro group is accomplished by a variety of methods, for example withIron in acetic acid (see Hudlicky, M., “Reductions in OrganicChemistry”, Ellis Horwood, Ltd., Chichester, UK, 1984). Subsequentheating at elevated temperatures effects cyclization to derivatives oftype (VI). This lactam can be alkylated by treatment with a suitablebase, such as sodium hydride, followed by addition of an alkyl halide,such as methyl iodide to afford derivatives of type (VII). Furtherelaboration of the aromatic ring can be accomplished by the followingprocedures. When R7=H, these derivatives (VI) or (VII) can beselectively brominated with NBS in DMF at 0° C. to afford bromoarylderivatives of type (VIII). Those skilled in the art will recognize theutility of aryl bromides of type (VIII) in allowing for the coupling ofthis moiety with an arylboronic acid to afford biaryl derivatives oftype (IX). This transformation, commonly known as a Suzuki couplingisutilized to afford many types of functionalized derivatives. For areview and leading references of palladium catalyzed cross couplingreactions, see Miyaura, N., Suzuki, A., Chem. Rev., 1995, 2457. One suchprocedure entails treatment of the aryl bromide (VIII) with afunctionalized aryl boronic acid in the presence of a catalytic Pd(0)species, such as Pd(PPh₃)₄, Pd(PPh₃)₂Cl₂, Pd(OAc)₂, Pd₂(dba)₃ and asuitable ligand such as PPh₃, AsPh₃, etc., or other such Pd(O) catalyst,and a base such as Na₂CO₃ or Et₃N in a suitable solvent such as DMF,toluene, THF, DME or the like, to afford the coupled derivative (IX).Alternately, reduction of the lactam carbonyl of (VIII) with a reducingagent such as Dibal or BH₃, followed by Suzuki coupling affordsderivatives of type (X). In addition, formation of the aryl boronic acidfrom the bromine derivative (VIII) (i.e. (I, R⁷=B(OH)₂)) would allow forgreater diversity in the subsequent coupling of this aryl boronic acidwith commercially available haloaromatic derivatives in a similar Suzukicoupling strategy as described above to afford the derivatives of type(IX) and (X).

[1579] Formation of nitrogen linked biaryl derivatives is described inScheme 2. Treatment of arylbromide derivatives of type (VIII) withdiphenylmethylimine under Pd₂(dba)₃, BINAP catalyzed conditions followedby basic hydrolysis (NH₂OH—HCl, NaOAc, MeOH) of the imine affords theprimary aniline derivative (XI). Coupling of these anilines with variousarylbromides under Pd(0) catalyzed conditions affords the amine linkedbiaryl derivatives of type (XII) (see A. S. Guram, R. A. Rennels and S.L. Buchwald, Angew. Chem. Int. Ed. Engl., 1995,34,1348). These lactamderivatives can also be alkylated and subsequently reduced to the amine,as previously described, then coupled to afford derivatives of type(XIII).

[1580] Selective bromination of the alternate sites (R⁶, R⁸, and R⁹) ofderivatives of type (VII) (Scheme 1) is not possible under the currentprotocol. Initiating the synthesis in Scheme 1 of derivatives of type(VIII) with a halogen or nitro group at R⁶, R⁸, or R⁹, allows forpreparation of R⁶, R⁸, and R⁹ biaryl or N-aryl derivatives. Use of anarylnitro group to effect this coupling either directly via thediazonium salt derivative or indirectly through transformatin of thediazonium salt to an aryl bromide via Sandoz reaction conditions (seeLarock, R. C., Comprehensive Organic Transformations, VCH Publishers,New York, 1989) is an alternate route to these R⁶, R⁸, and R⁹substituted derivatives. Scheme 3 illustrates an example of thisapproach (R⁸=Br) to aryl and N-aryl derivatives of type (XIV) via theprotocol described above for Schemes 1 and 2.

[1581] More highly substituted nitrobenzenes starting materials can beobtained by traditional synthetic manipulation (i.e aromaticsubstitution) and are known by those in the art (see Larock, R. C.,Comprehensive Organic Transformations , VCH Publishers, New York, 1989).

[1582] The corresponding enantiomers can be isolated by separation ofthe racemic mixture of (I) on a chiral stationary phase column utilizingnormal or reverse phase HPLC techniques. Alternatively, a diastereomericmixture of (I) can be prepared by treatment of (I, R¹=H) with anappropriate chiral acid (or suitably activated derivative), for exampledibenzoyl tartrate or the like (see, for example, Kinbara, K., et. al.,J. Chem. Soc., Perkin Trans. 2, 1996, 2615; and Tomori, H., et. al.,Bull. Chem. Soc. Jpn., 1996, 3581). The diastereomers would then beseparated by traditional techniques (i.e. silica chromatography,crystallization, HPLC, etc) followed by removal of the chiral auxiliaryto afford enantiomerically pure (I).

[1583] In the cases where the piperidine nitrogen has been protected inthe course of the synthesis (i.e. R¹=Boc, Bn, CBZ, CO₂R), it may beremoved under a variety of conditions as described in Greene, T. W.,Wuts, P. G. W., “Protective Groups in Organic Synthesis, 2nd Edition”,John Wiley and Sons, Inc., New York, pages 309-405, 1991. The freesecondary amine is targeted directly or can be further alkylated, forexample, by treatment with a suitably substituted alkyl halide (R¹Cl, orR¹I) and a base, such as NaH or KH, to afford additional compounds oftype (I), as described, for example, by Glennon, R. A., et. al., Med.Chem. Res., 1996, 197.

[1584] An additional preparation of biaryl and/or NH-aryl linkedcompounds of type (IX), (X), etc. can be accomplished by preparation ofthe starting chloronitrophenyl compound with the required arylsubstitution in place. For instance, initiating the synthesis with aderivative of type (III) where R⁶, R⁷, R⁸, or R⁹ is an aryl or NH-arylsubstituent. Some of the methods for preparation of these startingmaterials has been described here and are known by those skilled in theart.

[1585] The preparation of the more highly substituted compounds of type(I-a) is shown in Scheme 4. A more detailed description of the varietyof ring systems utilized and the methods to prepare them are detailed inDM 7014. These methods are amenable to the preparation of derivatives oftype (I-a) described herein. Towards that end, alkylation of adichloronitrophenyl derivative of type (XV) with a nucleophilic alkylhalide (X═OH, SH, NHR) (as described by Kharasch, N., Langford, R. B.,J. Org. Chem., 1963, 1903) and a suitable base affords the nitroarylderivative (XVI). Elaboration of these functionalized derivatives iscarried out as before (see Scheme 1). Addition of the piperidinecarboxylic acid to afford derivatives of type (XVII) followed byreduction of the nitro functionality to give the cyclized derivatives(XVIII). The cyclization of the final ring can be accomplished on eitherthe lactam (XVIII) to afford the tetracycle of type (XIX) or priorreduction of the amide moiety of (XVIII) followed by base catalyzedcyclization to afford the tetracyclic amine derivatives (XX). Likewise,reduction of the lactam moiety of (XIX) with a suitable reducing agent,such as DIBAL or BH₃, yields the amine derivatives (XX). Subsequentincorporation of the aryl and NH-aryl functionalities on the aromaticring is performed as described previously. In addition, these morehighly functionalized, novel tetracyclic ring systems can be derivatizedon the aryl ring by a number of similar methods. There exists a widerange of procedures and protocols for functionalizing haloaromatics,aryldiazonium and aryltriflate compounds. These procedures are wellknown by those in the art and described, for example, by Stanforth, S.P., Tetrahedron, 1998, 263; Buchwald, S. L., et. al., J. Am. Chem. Soc.,1998, 9722; Stille, J. K., et. al., J. Am. Chem. Soc., 1984, 7500. Amongthese procedures are biaryl couplings, alkylations, acylations,aminations, and amidations. The power of palladium catalyzedfunctionalization of aromatic cores has been explored in depth in thelast decade. An excellent review of this field can be found in J. Tsuji,“Palladium Reagents and Catalysts, Innovations in Organic Synthesis”, J.Wiley and Sons, New York, 1995.

[1586] An alternate approach to the substituted fused anilines (I-a) isshown in Scheme 5. Using derivatives of type (VI) with R⁶═H, the lactamcan be reduced to the corresponding amine with DIBAL or the like.Subsequent base treatment, with for example NaH, and alkylation of theamine with, for example, a haloalkyl carboxylic acid (or equivalentactivated haloalkylcarboxylic acid, (i.e. acid halide, mixed anhydride,acrylic acid, acryloyl chloride, etc.)), affords the derivative (XXI)which when treated under Friedel-Crafts acylation conditions (see Ed. G.A. Olah, “Friedel-Crafts and Related Reactions”, J. Wiley and Sons, NewYork, 1964, Vol 3, Pts 1 and 2 or Chem. Rev., 1955, 229, or Olah, G. A.,“Friedel-Crafts Chemistry”, Wiley Interscience, New York, 1973, forvarying conditions and protocols), i.e. strong Lewis acids (AlCl₃,FeCl₃, etc.), affords the cyclic alkylphenones (XXII). Elaboration ofthis derivative by reduction of the ketone with a suitable reducingagent or Wittig olefination of the ketone by standard conditions shouldallow for extensive diversity in preparing compounds of type (XXIII).These and other conditions for these transformations are known by thoseskilled in the art and examples of these may be found in Larock, R. C.,Comprehensive Organic Transformations, VCH Publishers, New York, 1989.

[1587] Incorporation of nitrogen functionality into derivatives of type(XXII) can be accomplished in several ways. For example, Schmidtrearrangement (as described by Smith, P. A. S., J. Am. Chem. Soc., 1948,320) is effected by treatment of the carbonyl derivative (XXII) withNaN₃ and methanesulfonic acid to afford the bicyclic lactam (XXIV).Alternatively, this transformation may be carried out under Hoffmannrearrangement protocol (see, for example, Dike, S. Y., et. al., Bioorg.Med. Chem. Lett., 1991, 383), by initial formation of the oximederivative of (XXII) by treatment with hydroxylamine hydrochloride.Subsequent rearrangement to the lactam is efficiently accomplished byheating in polyphosphoric acid to afford the lactam (XXIV). Reduction ofthe lactam (XXIV) can be accomplished with a variety of reducing agents,for example, DIBAL, Red-Al and the like to afford the aniline (XXV).Alternatively, treatment of the lactam with dimethyltitanocene (Petasis,N., et.al.) followed by Pd/C catalyzed hydrogenation should afford theamine derivative (XXV) where R¹¹=Me. Standard conditions may be used foralkylation of the amine or lactam (R¹⁰) to afford more highlysubstituted derivatives of type (XXIV) and (XXV).

[1588] As was described previously, installation of an aryl or NH-arylmoiety on the aromatic ring of derivatives of type (XXII)-(XXV) can beaccomplished in a variety of ways, dependant upon the substitution ofthe aromatic ring.

[1589] Furthermore and as an extension of this approach to a rapidpreparation of a large array of biaryl, NH-aryl and aryl substitutedderivatives, these various bromide derivatives (i.e.VII and VIII andrelated teracyclic brominated derivatives) can be bound to a solidsupport. Suzuki couplings can then be carried out on solid support asillustrated in Scheme 6. As an example of this approach, treatment of anaryl bromide of derivatives of type (XXVI, R¹═CBz) with H₂ and Pd/C, toremove the CBz protecting group, followed by extraction from aqueousbase provides the free amine (XXVI, R¹═H). The free amine can be loadedonto a suitable solid support such as (XXVII) using conditions wellknown to those skilled in the art. Thus, p-nitrophenylchloroformate Wangresin (XXVII) which can be obtained commercially from sources such asNovabiochem, Inc. is swollen in a suitable solvent such as N-methylpyrrolidinone and treated with 1.5 equiv. of amine to afford thefunctionalized resin (XXVIII). Suzuki couplings are then carried out inarray format by treatment of resins (XXVIII) with a suitable palladiumsource such as Pd(PPh₃)₄ or Pd(dppf)Cl₂ and a suitable base such as 2Maqueous K₂CO₃ or Na₂CO₃ or triethylamine with an excess (typically 5equivalents) of an aryl boronic acid (procedures for solid-phase Suzukiand other palladium couplings are well-known by those in the art, seefor instance L. A. Thompson and J. A. Ellman, Chem. Rev. 1996, 96, (1),555-600). The coupling may be repeated to ensure complete conversion tothe desired coupled product. Cleavage from the solid support bytreatment with TFA affords the corresponding functionalized derivatives(XXIX) as their TFA salts.

[1590] One such method to prepare compounds of Formula (I) and (I-a)with substituted R¹ sidechains in a more direct manner is illustrated inScheme 7. Alkylation of the piperidine nitrogen (I or II, R¹═H) with ahaloalkyl ester, such as ClCH₂(CH₂)_(p)CO₂Me, in the presence of NaI orKI and a base such as K₂CO₃, Na₂CO₃ or the like, in dioxane or THF orother such solvent while heating (see Glennon, R. A., et. al., Med.Chem. Res., 1996, 197) affords the R¹ alkylated esters. Subsequentformation of the activated amides (XXX) is accomplished by treatment ofthe ester with N,O-dimethylhydroxylamine hydrochloride and a Lewis acidsuch as trimethylaluminum or triethylaluminum in toluene (see, forexample, Golec, J. M. C., et. al., Tetrahedron, 5 1994, 809) at 0° C.Treatment of the amide (XXX) with a variety of organometallic agents,such as Grignard reagents R²MgBr, alkyl and aryl lithium reagents etc.(see Sibi, M. P., et. al., Tetrahedron Lett., 1992, 1941; and moregenerally House, H. O., Modern Synthetic Reactions, W. A. Benjamin,Inc., Menlo Park, Calif., 1972), in a suitable solvent such as THF,ether, etc. at low temperatures affords the substituted ketones (XXXI).

[1591] It is understood that for substituents R⁷, R⁸, R⁹, and R¹, thecompounds of the present invention can be prepared in a number of wayswell known to one skilled in the art of organic synthesis. The compoundsof the present invention can be synthesized using the methods describedherein, together with synthetic methods known in the art of syntheticorganic chemistry, or variations thereon as appreciated by those skilledin the art. Additional methods include, but are not limited to, thosedescribed in U.S. Ser. No. 09/594,954 (filed Jun. 15, 2000); U.S. Ser.No. 09/595,250 (filed Jun. 15, 2000); and U.S. Ser. No. 09/594,008(filed Jun. 15, 2000); wherein all three references are herebyincorporated in their entirety herein by reference.

[1592] It is also understood that for substituents in positions R¹,R^(4a), R^(4b), R⁵, R⁶, R⁷, R⁸, R⁹, n, and X, the compounds of thepresent invention can be synthesized using additional methods describedin DuPont Pharmaceuticals U.S. Provisional Patent Applications U.S. Ser.No. 60/256,745 (filed Dec. 20, 2000) and U.S. Ser. No. 60/256,740 (filedDec. 20, 2000), hereby incorporated in their entirety herein byreference, together with synthetic methods known in the art of syntheticorganic chemistry, or variations thereon as appreciated by those skilledin the art.

EXPERIMENTALS Example 1

[1593] Preparation of8-(4-Methoxy-2-methylphenyl)-2,3,4,4a-tetrahydro-1H-pyrazino[1,2-a]quinoxalin-5(6H)-one.

[1594] Step A. To a solution of piperazine-2-carboxylic aciddihydrochloride (10 g, 49 mmol) in 40 ml water was added an aqueoussolution of sodium hydroxide (39 ml, 2.5 M). A solution of copper (II)sulfate pentahydrate (6.5 g, 26 mmol) in 80 ml water was added, and thedeep blue solution was cooled to 5° C. Sodium bicarbonate (5 g, 59 mmol)was added in one portion, followed by the dropwise addition ofbenzylchloroformate (7.7 ml, 54 mmol) in 40 ml dioxane over 10 minutes.Sodium bicarbonate was added as needed to maintain a basic solution. Thereaction was allowed to warm to rt and was stirred for 16 h. Theprecipitate was filtered and dried to afford4-carbobenzyloxypiperazine-2-carboxylic acid, copper chelate useddirectly in the next step.

[1595] Step B. To a solution of 4-carbobenzyloxypiperazine-2-carboxylicacid, copper chelate in 750 ml water was added ethylenediaminetetraceticacid, disodium salt, dihydrate (7.9 g, 21 mmol). The mixture was heatedto 80 ° C. for 3 h. The reaction mixture was then cooled to rt andconcentrated to dryness. The residue was dissolved in 100 ml DMSO.2-Fluoronitrobenzene (4.9 g, 35 mmol) and triethyl amine (20 ml, 143mmol) were added and the solution was heated to 60° C. for 16 h. Thedark reaction mixture was cooled to rt. Concentrated HCl was added tobring the pH to 3. The solution was then diluted with 500 ml water andthe aqueous layer was extracted with ethyl acetate. The combinedorganics were washed with water, dried over MgSO₄ and concentrated toafford 4-carbobenzyloxy-1-(2-nitrophenyl) piperazine-2-carboxylic acidused directly in the next step.

[1596] Step C. To a solution of the above4-carbobenzyloxy-1-(2-nitrophenyl)piperazine-2-carboxylic acid in 200 mlglacial acetic acid warmed to 60° C. was added iron powder (16 g) inportions. The reaction was heated at 60° C. for 3 h. The reaction wascooled to rt and 1N HCl was added. The resulting precipitate wasfiltered and dried. The crude material was dissolved in methylenechloride and passed through a plug of silica gel, eluting with 40% ethylacetate/hexanes. The filtrate was concentrated to afford3-carbobenzyloxy-2,3,4,4a-tetrahydro-1H-pyrazino[1,2-a]-quinoxalin-5(6H)-oneas a white solid (7.98 g, 68% over 3 steps). ¹H NMR (CDCl₃, 300 MHz)δ7.32-7.38 (m, 5H), 7.00-7.06 (m, 1H), 6.86-6.91 (m, 1H), 6.78-6.80 (m,2H), 5.18-5.19 (m, 2H), 4.75 (m, 1H), 4.31 (m, 1H), 3.59-3.63 (m, 1H),3.50 (dd, J=11.1, 3.6 Hz, 1H), 3.06-3.14 (m, 2H), 2.72-2.81 (m, 1H),1.65 (s, 1H) ppm. MS (ESI) m/z=338 [M+H].

[1597] Step D. To a solution of3-carbobenzyloxy-2,3,4,4a-tetrahydro-1H-pyrazino[1,2-a]-quinoxaline-5(6H-one(4.0 g, 11.9 mmol) in 30 ml DMF cooled to 0° C. was added a solution ofN-bromosuccinimide in 30 ml DMF over 20 minutes. The orange reaction wasstirred at 0° C. for an additional 1.5 h. Water was added and theaqueous layer was extracted with ethyl acetate. The combined organicswere washed with water, dried over MgSO₄, and concentrated to a yellowsolid. The crude material was recrystallized from hot ethyl acetate togive 8-bromo-3-carbobenzyloxy-2,3,4,4a-tetrahydro-1H-pyrazino[1,2-a]-quinoxalin-5(6H)-one as a white solid (3.84 g, 78% recrystallizedyield). ¹H NMR (CDCl₃, 300 MHz) δ7.32-7.7.38 (m, 5H), 7.12 (dd, J=8.8,2.2 Hz, 1H), 6.92 (d, J=2.1, 1H), 6.62-6.65 (m, 1H), 5.18 (m, 2H), 4.74(m, 1H), 4.31 (m, 1H), 3.47-3.57 (m, 2H), 3.06-3.13 (m, 2H), 2.73-2.96(m, 1H), 1.61 (s, 1H) ppm. MS (ESI) m/z=416 [M+H]+.

[1598] Step E: Coupling procedure: To a solution of8-bromo-3-carbobenzyloxy-2,3,4,4a-tetrahydro-1H-pyrazino[1,2-a]-quinoxalin-5(6H)-one (415 mg, 1 mmol) in benzene (10 ml) wasadded 2-methyl-4-methoxybenzene boronic acid (332 mg, 2 mmol), 2M Na₂CO₃(2 ml), and dichlorobis(triphenylphosphine)palladium(II) (35 mg, 0.05mmol). The reaction mixture was degassed and heated to reflux for 16 h.The reaction mixture was cooled to rt and concentrated to a blackresidue. The residue was taken up in ethyl acetate and filtered toafford3-carbobenzyloxy-8-(4-methoxy-2-methylphenyl)-2,3,4,4a-tetrahydro-1H-pyrazino[1,2a]quinoxalin-5(6H) -one (297 mg, 65%).

[1599] Step F: Deprotection procedure: To a solution of3-carbobenzyloxy-8-(4-methoxy-2-methylpheny)-2,3,4,4a-tetrahydro-1H-pyrazino [1,2-a]quinoxalin-5(6H) -one (0.38 mmol) in 6ml absolute ethanol was added 10% Pd/C (150 mg) and excess cyclohexene(3 ml). The black reaction mixture was heated to reflux. After 5 h, themixture was cooled to rt and filtered through a pad of celite, washingheavily with methanol. The filtrate was concentrated to a colorlessresidue. The crude material was purified by radial PLC (1 mm plate, loadand elute with methanol) to give the title compound as a colorless oil(30 mg, 24%). ¹H NMR (CDCl₃, 300 MHz) δ7.12 (d, J=8.1 Hz, 1H), 6.95 (dd,J=8.5, 1.9 Hz, 1H), 6.76-6.82 (m, 3H), 6.67 (d, J=1.8 Hz, 1H), 3.83 (s,3H), 3.53-3.67 (m, 3H), 3.18 (m, 1H), 2.79-3.01 (m, 3H), 2.26 (s, 3H)ppm. MS (ESI) m/z =324.2 [M+H]⁺.

Example 2

[1600] Preparation of8-(4-Methoxy-2-methylphenyl)-2,3,4,4a,5,6-hexahydro-1H-pyrazino[1,2-a]quinoxaline.

[1601] Step A: To a solution of8-bromo-3-carbobenzyloxy-2,3,4,4a-tetrahydro-1H-pyrazino [1,2-a]-quinoxalin-5(6H-)-one (2.15 g, 5.2 mmol) in 30 ml THF cooled to 0°C. was added a solution of BH₃-THF complex (16.25 ml, 16.25 mmol, 1M inTHF) . The reaction was allowed to slowly warm to rt over 25 minutes andwas heated to ref lux. After 1.5 h, the reaction was cooled to rt.Methanol was added and the mixture was concentrated to a yellow residue.This was repeated. The crude material was purified by columnchromatography using a Biotage© Flash 40i (4.0×15.0 cm column, load andelute with methylene chloride) to give8-bromo-3-carbobenzyloxy-2,3,4,4a,5,6-hexahydro-1H-pryazino[1,2-a]quinoxaline as a white solid (1.26 g, 60%). ¹H NMR (CDCl₃, 300MHz) δ7.34-7.38 (m, 5H), 6.72-6.75 (dd, J=8.8, 2.2 Hz, 1H) ) , 6.53-6.59(m, 2H) , 5.16 (s, 2H), 4.19 (m, 2H), 3.77 (bs, 1H), 3.63 (m, 1H), 3.35(m, 1H), 3.19-3.25 (m, 1H), 3.00-3.08 (m, 1H), 2.68-2.75 (m, 2H), 1.58(s, 1H) ppm. MS (ESI) m/z=402 [M+H]⁺.

[1602] Step B: General Coupling procedure: To a solution of8-bromo-3-carbobenzyloxy-2,3,4,4a5,6-hexahydro-1H-pryazino[1,2-a]quinoxaline (0.5 mmol) in 5 ml benzene was added boronic acid(1.0 mmol) , 2 M aqueous solution of Na₂CO₃ (1 ml), and dichlorobis(triphenylphosphine)palladium(II) (0.025 mmol). The reaction mixture wasdegassed thoroughly and heated to reflux for 16 h. The black reactionmixture was then cooled to rt and concentrated to a black residue. Thiswas dissolved in methylene chloride and passed through a plug of silicagel, eluting with 40% ethyl acetate/hexanes. The filtrate wasconcentrated to a residue. The crude material was purified by radial PLC(1 mm plate, load and elute with 20% ethyl acetate/hexanes) to give thecoupled product as a white foam.

[1603] Step C: General Deprotection procedure: To a solution of the CBzprotected coupled product (0.21 mmol) in 4 ml absolute ethanol was added10% Pd/C and excess cyclohexene (2 ml). The black reaction mixture washeated to reflux. After 4 h, the mixture was cooled to rt and filteredthrough a pad of celite, washing heavily with methanol. The filtrate wasconcentrated to a colorless residue. The crude material was purified byradial PLC (1 mm plate, load and elute with methanol) to give thesecondary amine as a white foam.

[1604] The title compound was prepared from8-bromo-3-carbobenzyloxy-2,3,4,5,6-hexahydro-1H-pyrazino[1,2-a]quinoxaline and the required boronic acid by the generalprocedure of steps B and C given above in 35% overall yield. ¹H NMR(CDCl₃, 300 MHz) δ7.12-7.15 (m, 1H), 6.72-6.78 (m, 3H), 6.60 (dd, J=8.1,2.1 Hz, 1H), 6.43 (d, J=2.1 Hz, 1H), 3.81 (s, 3H), 3.66-3.74 (m, 2H),3.29-3.31 (m, 2H), 3.15-3.19 (m, 1H), 2.93-3.11 (m, 3H), 2.69-2.76 (m,1H), 2.52-2.59 (m, 1H), 2.27 (s, 3H) ppm. MS (ESI) m/z=310 [M+H]⁺.

Example 3 Preparation of8-[4-Methoxy-2-(trifluoromethyl)phenyl]-2,3,4,4a,5,6-hexahydro-1H-pyrazino [1,2-a]quinoxaline.

[1605]

[1606] The title compound was prepared from8-bromo-3-carbobenzyloxy-2,3,4,4a-5,6-hexahydro-1H-pyrazino[1,2-a]quinoxaline and the required boronic acid by the generalprocedure of Example 2, Steps B and C in 27% overall yield. ¹H NMR(CDCl₃, 300 MHz) δ7.20-7.25 (m, 2H), 7.02 (dd, J=8.7, 2.7 Hz, 1H), 6.71(d, J=8.4 Hz, 1H), 6.60 (dd, J=8.1, 1.5 Hz, 1H), 6.44 (d, J=1.5 Hz, 1H),3.861 (s, 3H), 3.67-3.71 (m, 2H), 3.29-3.31 (m, 2H), 2.97-3.20 (m, 4H),2.70-2.77 (m, 1H), 2.55 (m, 1H) ppm. MS (ESI) m/z=364 [M+H]⁺.

Example 4 Preparation of8-(2-Methylphenyl)-2,3,4,4a,5,6-hexahydro-1H-pyrazino[1,2-a]quinoxaline.

[1607]

[1608] The title compound was prepared from8-bromo-3-carbobenzyloxy-2,3,4,4a,5,6-hexahydro-1H-pyrazino[1,2-a]quinoxaline and the required boronic acid by the generalprocedure of Example 2, Steps B and C in 24% overall yield. ¹H NMR(CDCl₃, 300 MHz) δ7.19-7.26 (m, 4H) , 6.55 (dd, J=8.2, 1.9 Hz, 1H), 6.46(d, J=1.8 Hz, 1H), 3.69-3.73 (m, 1H), 2.94-3.32 (m, 6H), 2.76-2.80 (m,1H), 2.58 (m, 1H), 2.29 (s, 3H) ppm. MS (ESI) m/z=280 [M+H]⁺.

Example 5 Preparation of8-(3-Methylphenyl)-2,3,4,4a,5,6-hexahydro-1H-pyrazino[1,2-a]quinoxaline.

[1609]

[1610] The title compound was prepared from8-bromo-3-carbobenzyloxy-2,3,4,4a,5,6-hexahydro-1H-pyrazino[1,2-a]quinoxaline and the required boronic acid by the generalprocedure of Example 2, Steps B and C in 12% overall yield. ¹H NMR(CDCl₃, 300 MHz) δ7.28-7.33 (m, 3H), 7.06-7.08 (m, 1H), 6.91 (dd, J=8.4,1.8, 1 H), 6.73-6.78 (m, 2H), 3.68-3.72 (m, 1H), 3.27-3.48 (m, 2H),3.15-3.19 (m, 1H), 2.93-3.07 (m, 3H), 2.70-2.77 (m, 1H), 2.53-2.61 (m,1H), 2.38 (s, 3H) ppm. MS (ESI) m/z=280 [M+H]⁺.

Example 6 Preparation of8-(4-Methylphenyl)-2,3,4,4a,5,6-hexahydro-1H-pyrazino[1,2-a]quinoxaline.

[1611]

[1612] The title compound was prepared from8-bromo-3-carbobenzyloxy-2,3,4,4a,5,6-hexahydro-1H-pyrazino[1,2-a]quinoxaline and the required boronic acid by the generalprocedure of Example 2, Steps B and C in 10% overall yield. ¹H NMR(CDCl₃, 300 MHz) δ7.41 (d, J=8.4, 1H), 7.18 (d, J=8.1, 1H), 6.91 (dd,J=8.1, 2.1 Hz, 1H), 6.77 (d, J=8.4 Hz, 1H), 6.72 (d, J=2.1, 1H), 3.78(m, 1H), 3.67-3.71 (m, 1H), 3.29-3.32 (m, 2H), 3.15-3.19 (m, 1H),2.92-3.10 (m, 3H, 2.67-2.76 (m, 1H), 2.52-2.62 (m, 1H), 2.36 (s, 3H)ppm. MS (ESI) m/z=280 [M+H]⁺.

Example 7 Preparation of8-[4-Fluoro-2-(trifluoromethyl)phenyl]-2,3,4,4a,5,6-hexahydro-1H-pyrazino[1,2-a]quinoxaline.

[1613]

[1614] The title compound was prepared from8-bromo-3-carbobenzyloxy-2,3,4,4a,5,6-hexahydro-1H-pyrazino[1,2-a]quinoxaline and the required boronic acid by the generalprocedure of Example 2, Steps B and C in 5% overall yield. ¹H NMR(CDCl₃, 300 MHz) δ7.69-7.72 (m, 1H), 7.64 (m, 1H), 7.18 (m, 1H), 6.85(dd, J=8.5, 2.2, 1H), 6.77 (d, J=8.4, 2.1 Hz, 1H), 6.66 (d, J=2.1 Hz,1H), 3.83 (m, 1H), 3.68-3.71 (m, 1H), 2.98-3.36 (m, 6H), 2.70-2.79 (m,1H), 2.57-2.61 (m, 1H) ppm. MS (ESI) m/z=352 [M+H]⁺.

Example 8 Preparation of 9- (4-Methylphenyl)-2,3,4,4a,5,6-hexahydro-1H-pyrazino [1,2-a]quinoxaline.

[1615]

[1616] Step A. To a solution of piperazine-2-carboxylic aciddihydrochloride (10 g, 49 mmol) in 40 ml water was added an aqueoussolution of sodium hydroxide (39 ml, 2.5 N). A solution of copper (II)sulfate (6.5 g, 26 mmol) in 80 ml water was added, and the deep bluesolution was cooled to 5° C. Sodium bicarbonate (5 g, 59 mmol) was addedin one portion, followed by the dropwise addition of benzylchloroformate(7.7 ml, 54 mmol) in 40 ml dioxane over 10 minutes. Sodium bicarbonatewas added as needed to maintain a basic solution. The reaction wasallowed to warm to rt and was stirred for 16 h. The precipitate wasfiltered and dried to afford 4-carbobenzyloxypiperazine-2-carboxylicacid, copper chelate residue used directly in the next step.

[1617] Step B. To a solution of 4-carbobenzyloxypiperazine-2-carboxylicacid, copper chelate in 750 ml water was added ethylenediaminetetraceticacid, disodium salt, dihydrate (7.9 g, 21 mmol) and the blue mixture washeated to 80° C. for 3 h. The reaction mixture was cooled to rt andconcentrated to dryness. The blue residue was dissolved in 100 ml DMSO.2,4-dichloronitrobenzene (6.66 g, 35 mmol) and triethyl amine (20 ml,143 mmol) were added and the solution was heated to 60° C. for 16 h. Thedark reaction mixture was cooled to rt. Concentrated HCl was added to pH=3. The solution was then diluted with 500 ml water and the aqueouslayer was extracted with ethyl acetate. The combined organics werewashed with water, dried over MgSO₄ and concentrated to afford4-carbobenzyloxy-l-(4-chloro-2-nitrophenyl)piperazine-2-carboxylic acidas a yellow residue used directly in the next step.

[1618] Step C. To a solution of the above residue4-carbobenzyloxy-l-(4-chloro-2-nitrophenyl)piperazine-2-carboxylic acidin 200 ml glacial acetic acid warmed to 60° C. was added iron powder (14g) in portions. The reaction was heated at 60° C. for 3 h. The reactionwas cooled to rt and 1N HCl was added. The resulting precipitate wasfiltered and dried. The crude material was dissolved in methylenechloride and passed through a plug of celite. The filtrate wasconcentrated to a dark red residue. This was purified by the Biotage 40i(4.0×15.0 cm column, load methylene chloride, elute 30-50% ethylacetate/hexanes) to give9-chloro-3-carbobenzyloxy-2,3,4,4a-tetrahydro-1H-pyrazino[1,2-a]-quinoxalin-5(6H)-oneas an off-white solid (4.8 g, 37% yield over 3 steps). ¹H NMR (CDCl₃,300 MHz) δ7.32-7.37 (m, 5H), 6.82-6.85 (m, 1H), 6.68-6.75 (m, 2H), 5.18(m, 2H), 4.73 (m, 1H), 4.31 (m, 1H), 3.49-3.54 (m, 2H), 3.07 (m, 2H),2.74-2.81 (m, 1H) ppm. MS (ESI) m/z=372 [M+H]⁺.

[1619] Step D. To a solution of9-chloro-3-carbobenzyloxy-2,3,4,4a-tetrahydro-1H-pyrazino[1,2-a]-quinoxalin-5(6H)-one (1.45 g, 3.9 mmol) in 50 ml THF was added asolution of borane-THF complex (1M in THF, 12.2 ml, 12.2 mmol). After 15min, the reaction was heated to reflux. After MS showed the absence ofstarting material, the reaction mixture was cooled to rt. Methanol wasadded and the solution concentrated to a yellow residue. This wasrepeated and the crude material was purified by column chromatographyusing a Biotage© Flash 40i (4.0×15.0 cm column, load with methylenechloride, elute with 25-30% ethyl acetate/hexanes) to give9-Chloro-3-carbobenzyloxy-2,3,4,4a,5,6-hexahydro-1H-pyrazino[1,2-a]quinoxalineas an off-white solid (898.3 mg, 65%). ¹H NMR (CDCl₃, 300 MHz)δ7.32-7.38 (m, 5H), 6.56-6.66 (m, 2H), 6.37-6.40 (m, 1H), 5.16 (s, 2H),4.19 (m, 2H), 3.61-3.71 (m, 2H), 3.33-3.36 (m, 1H), 3.05-3.23 (m, 2H),2.72-2.79 (m, 2H) ppm. MS (ESI) m/z=358 [M+H]⁺.

[1620] Step E. To a two-necked round bottom flask charged with argon wasadded palladium (II) acetate (4 mg, 0.0195 mmol),2-dicyclohexylphosphino-2′-(N,N-dimethylamino)biphenyl (10 mg, 0.02925mmol), p-tolylboronic acid (80 mg, 0.59 mmol), potassium fluoride (68mg, 1.17 mmol), and9-Chloro-3-carbobenzyloxy-2,3,4,4a,5,6-hexahydro-1H-pyrazino[1,2-a]quinoxaline(140 mg, 0.39 mmol). 1 ml of degassed 1,4- dioxane was added and thereaction was degassed and heated to 100° C. for 20 h. The reactionmixture was cooled to rt and diluted with ether. 1N NaOH was added andthe aqueous layer was extracted with ethyl acetate. The combinedorganics were washed with brine, dried over MgSO₄, and concentrated to ayellow residue. The crude material was purified by radial PLC (1 mmplate, load with methylene chloride, elute with 20- 40% ethylacetate/hexanes) to give9-(4-methylphenyl)-2,3,4,4a,5,6-hexahydro-1H-pyrazino[1,2-a]quinoxalineas a yellow foam (0.23 mmol, 60%).

[1621] Step F. To a solution of the9-(4-methylphenyl)-2,3,4,4a,5,6-hexahydro-1H-pyrazino[1,2-a]quinoxaline(96 mg, 0.23 mmol) in 4 ml absolute ethanol was added 10% Pd/C (95 mg)and excess cyclohexene (2 ml). The black reaction mixture was heated toreflux. After 6 h, the mixture was cooled to rt and filtered through apad of celite, washing heavily with methanol. The filtrate wasconcentrated to a yellow oil. This was purified by reverse phase HPLC togive the title compound as the di-TFA salt(30 mg, 26%). ¹H NMR (CD₃OD,300 MHz) δ6.87-7.44 (m, 7H), 3.24-3.43 (br m, 6 H), 2.95 (br m, 1H),2.34-2.44 (br m, 2 H), 1.99 (s, 3H) ppm. MS (ESI) m/z=280.3 [M+H]⁺.

UTILITY

[1622] The compounds of the present invention have therapeutic utilityfor illnesses or disorders involving the neurotransmitter serotonin(5-hydroxy tryptamine or 5-HT) and either agonism or antagonism of 5-HT2receptors, as demonstrated by the assays described below. Therapeuticutility for these illnesses or disorders could involve numerousbiological processes affected by serotonin including, but not limitedto, appetite, mood, sleep, sexual activity, and arterial constriction.These biological processes may also be important to numerous centralnervous system (CNS) disorders including those related to the affectivedisorders of depression, anxiety, psychosis, and schizophrenia, as wellas, disorders of food intake such as anorexia, bulemia, and obesity. Thecompounds of the present invention potentially have therapeutic utilityin other conditions in which serotonin has been implicated, such asmigraine, attention deficit disorder or attention deficit hyperactivitydisorder, addictive behavior, and obsessive-compulsive disorder, as wellas, conditions associated with cephalic pain, social phobias, andgastrointestinal disorders such as dysfunction of the gastrointestinaltract motility. Lastly, compounds of the present invention potentiallyhave therapeutic utility in neurodegenerative diseases and traumaticconditions represented by the examples of Alzheimer's disease andbrain/spinal cord trauma.

[1623] The pharmacological analysis of each compound for eitherantagonism or agonism of at 5-HT2A and 5-HT2C receptors consisted of invitro and in vivo studies. In vitro analyses included K_(i)determinations at 5-HT2A and 5-HT2C receptors and an assessment offunctional (i.e., agonism or antagonism) activity at each receptor classby IP3 hydrolysis assays. Additional receptor assays were conducted toevaluate receptor specificity of 5-HT2A and 5-HT2C receptors overmonoamine and nuisance receptors (e.g. histamine, dopamine, andmuscarinic). A compound is considered active as a 5-HT2A antagonist or a5-HT2C agonist if it has an IC₅₀ value or a K_(i) value of less thanabout 50 micromolar; preferably less than about 0.1 micromolar; morepreferably less than about 0.01 micromolar. Using the assays disclosedherein, compounds of the present invention have been shown to have anIC₅₀ value of less than about 50 micromolar for 5-HT2A antagonism or5-HT2C agonism.

[1624] In vivo assays assessed compound activity in a variety ofbehavioral paradigms including quipazine head twitch, acute and chronicfeeding models, anxiety and depression models (learned-helplessness,elevated plus maze, Geller-Siefter, conditioned taste aversion, tastereactivity, satiety sequence). In aggregate, these models reflectactivity as a 5-HT2A antagonist (quipazine head twitch, depressionmodels) or 5-HT2C agonist (feeding models, anxiety models, depressionmodels) and provide some indication as to bioavailability, metabolismand pharmacokinetics.

[1625] Radioligand binding experiments were conducted on recombinanthuman 5-HT2A and 5-HT2C receptors expressed in HEK293E cells. Theaffinities of compounds of the present invention to bind at thesereceptors is determined by their capacity to compete for[¹²⁵I]-1-(2,5-dimethoxy-4-iodophenyl)-2-amino-propane (DOI) binding atthe 5-HT2A or 5-HT2C. General references for binding assays include 1)Lucaites V L, Nelson D L, Wainscott D B, Baez M (1996) Receptor subtypeand density determine the coupling repertoire of the 5-HT2 receptorsubfamily. Life Sci., 59(13):1081-95. J Med Chem 1988 Jan;31(1):5-7; 2)Glennon R A, Seggel M R, Soine W H, Herrick-Davis K, Lyon R A, Titeler M(1988) [125I]-1-(2,5-dimethoxy-4-iodophenyl)-2-amino-propane: aniodinated radioligand that specifically labels the agonist high-affinitystate of 5-HT2 serotonin receptors. J Med. Chem. 31(1):5-7 and 3)Leonhardt S, Gorospe E, Hoffman B J, Teitler M (1992) Molecularpharmacological differences in the interaction of serotonin with5-hydroxytryptamine1C and 5-hydroxytryptamine2 receptors. MolPharmacol., 42(2):328-35.

[1626] The functional properties of compounds (efficacy and potency)were determined in whole cells expressing 5-HT2A or 5-HT2C receptors byassessing their ability to stimulate or inhibit receptor-mediatedphosphoinositol hydrolysis. The procedures used are described below.

In Vitro Binding Assays

[1627] Stable expression of 5-HT2A and 5-HT2C receptors in HEK293Ecells.

[1628] Stable cell lines were generated by transfecting 293EBNA cellswith plasmids containing human 5-HT2A , 5-HT2B, or 5-HT2C (VNV editedisoform) cDNA using calcium phosphate. These plasmids also contained thecytomegalovirus (CMV) immediate early promoter to drive receptorexpression and EBV oriP for their maintenance as an extrachromosomalelement, and the hph gene from E. Coli to yield hygromycin B resistance(Horlick et al., 1997). Transfected cells were maintained in Dulbecco'sModified Eagle medium (DMEM) containing dialyzed 10% fetal bovine serumat 37° C. in a humid environment (5% CO₂) for 10 days. The 5-HT2A cellswere adapted to spinner culture for bulk processing whereas it wasnecessary to maintain the other lines as adherent cultures. On the dayof harvest, cells were washed in phosphate-buffered saline (PBS),counted, and stored at −80° C.

Membrane Preparation

[1629] On the day of assay, pellets of whole cells (containingapproximately 1×108 cells) expressing the 5-HT2A or 5-HT2C receptor werethawed on ice and homogenized in 50 mM Tris HCl (pH 7.7) containing 1.0mM EDTA using a Brinkman Polytron (PT-10, setting 6 for 10 sec). Thehomogenate was centrifuged at 48,000×g for 10 min and the resultingpellet washed twice by repeated homogenization and centrifugation steps.The final pellet was resuspended in tissue buffer and proteindeterminations were made by the bichichoninic acid (BCA) assay (PierceCo., Ill.) using bovine serum albumin as the standard.

[1630] Radioligand binding assays for the 5-HT2A ,and 5-HT2C receptors.

[1631] Radioligand binding studies were conducted to determine thebinding affinities (KI values) of compounds for the human recombinant5-HT2A, 5-HT2B, and 5-HT2C receptors (Fitzgerald et al., 1999). Assayswere conducted in disposable polypropylene 96-well plates (Costar Corp.,Cambridge, Mass.) and were initiated by the addition of 5-HT2A , 5-HT2B,or 5-HT2C membrane homogenate in tissue buffer (10-30 (g/well) to assaybuffer (50 mM Tris HCl, 0.5 mM EDTA, 10 mM pargyline, 10 mM MgSO₄, 0.05%ascorbic acid, pH 7.5) containing [¹²⁵I]DOI for the 5-HT2A and 5-HT2Creceptors (0.3-0.5 nM, final) or [³H]LSD (2-2.5 nM, final) for the5-HT2B receptor, with or without competing drug (i.e, newly synthesizedchemical entity). For a typical competition experiment, a fixedconcentration of radioligand was competed with duplicate concentrationsof ligand (12 concentrations ranging from 10 picomolar to 10micromolar). The reaction mixtures were incubated to equilibrium for 45min at 37° C. and terminated by rapid filtration (cell harvester;Inotech Biosystems Inc., Lansing, Mich.) over GFF glass-fiber filtersthat had been pre-soaked in 0.3% polyethyleneimine. Filters were washedin ice-cold 50 mM Tris HCl buffer (pH 7.5) and then counted in a gammacounter for the 5-HT2A and 5-HT2C assays, or by liquid scintillationspectroscopy for the 5-HT2B assay.

[1632] Phosphoinositide hydrolysis studies.

[1633] The ability of newly synthesized compounds to stimulatephosphoinositide (PI) hydrolysis was monitored in whole cells using avariant (Egan et al., 1998) of a protocol described previously (Berridgeet al., 1982). HEK293E cells expressing the human 5-HT2A, 5-HT2B, or5-HT2C receptor were lifted with 0.5 mM EDTA and plated at a density of100,000/well onto poly-D-lysine-coated 24-well plates (Biocoat; BectonDickinson, Bedford, Mass.) in Dulbecco's modified Eagle's serum (DMEM;Gibco BRL) containing high glucose, 2 mM glutamine, 10% dialyzed fetalcalf serum, 250 (g/ml hygromycin B, and 250(g/ml G418. Following a 24-48hr period, the growth media was removed and replaced with DMEM withoutfetal calf serum and inositol (Gibco BRL). The cells were then incubatedwith DMEM (without serum and inositol) containing a final concentrationof 0.5 uCi/well myo-[³H]inositol for 16-18 hr. Following thisincubation, the cells were washed with DMEM (without serum or inositol)containing 10 mM LiCl and 10 (M pargyline and then incubated for 30 minwith the same media but now containing one of several test compounds.Reactions were terminated by aspirating the media and lysing the cellsby freeze-thaw. [³H]phosphoinositides were extracted withchloroform/methanol (1:2 v/v), separated by anion exchangechromatography (Bio-Rad AGI-X8 resin), and counted by liquidscintillation spectroscopy as described previously (Egan et al., 1998).

[1634] Data analyses

[1635] The equilibrium apparent dissociation constants (Ki's) from thecompetition experiments were calculated using an iterative nonlinearregression curve-fitting program (GraphPad Prism; San Diego, Calif.).For the PI hydrolysis experiments, EC50's were calculated using aone-site ‘pseudo’ Hill model: y=((Rmax-Rmin)/(1+R/EC50)nH))+Rmax whereR=response (DeltaGraph, Monterey, Calif.). Emax (maximal response) wasderived from the fitted curve maxima (net IP stimulation) for eachcompound. Intrinsic activity (IA) was determined by expressing the Emaxof a compound as a percentage of the Emax of 5-HT (IA=1.0).

In Vivo Experiments for Serotonergic Ligands. Preclinical Efficacy,Potency, and Side Effect Liability.

[1636] a) Anti-Serotonin Efficacy.

[1637] Antagonism of Quipazine-Induced Head Twitch in Rat. Quipazine, anagonist at 5-HT receptors, produces a characteristic head twitchresponse in rats. 5-HT receptor antagonists effectively antagonize this5-HT agonist-induced behavioral effect (Lucki et al., 1984).Accordingly, the quipazine-induced head twitch model in rat can functionas an in vivo behavioral correlate to 5-HT receptor binding. Compoundsare administered 30 minutes before behavioral testing (and 25 minutesbefore quipazine), and a dose-related antagonism of the quipazineresponse is determined.

[1638] b) Antipsychotic Efficacy.

[1639] Inhibition of the Conditioned Avoidance Response (CAR) in Rat.Rats are trained to consistently avoid (by climbing onto a polesuspended from the ceiling of the test chamber) an electric foot shock(0.75 mA) delivered to the grid floor of the testing chamber. Allantipsychotic drugs effectively inhibit this conditioned avoidanceresponse (Arnt, 1982). The ability of a compound to inhibit thisresponse is used to determine the antipsychotic efficacy of potentialdrug candidates.

[1640] c) Extrapyramidal Side Effect Liability.

[1641] Induction of Catalepsy in Rat. Typical antipsychotic drugsproduce extrapyramidal side effects (EPS) at clinically effective doses.The most widely accepted preclinical indicator of EPS liability inhumans is a drug-induced catalepsy syndrome in rat (Costall and Naylor,1975), a condition whereby the animal will remain immobile in anexternally imposed posture (analogous to a catatonic stupor in humans).Rats are tested for induction of catalepsy in a dose-response test afteroral administration of compounds.

[1642] d) CNS penetration; In vivo brain receptor occupancy.

[1643] In Vivo Binding. To determine the level of in vivo receptoroccupancy, an in vivo receptor binding protocol is used. This procedureuses an appropriate radioligand to label the receptor of interest. Forexample, to measure both Dopamine D2 and 5-HT2A receptors in vivo, onecan use ³H—N-methyl spiperone (³H -NMSP), (Frost, et. al. 1987) Theprocedure uses rats (or mice) fasted overnight. To measure the effectsof compounds on the receptors of interest, compounds are dosed, usuallyp.o. for example in 2 microliters/gram body weight in 0.25% Methocelsuspension. The radiolabeled compound (in this example, ³H-NMSP) isadministered by i.v. tail vein injection (10 microcuries label/200 gramrat). Time course experiments are used to determine the optimal time ofbinding for both the radiolabeled and unlabeled compound. These optimaltime frames are used for all subsequent dose-response experiments. Afterthe appropriate time frame of compound/radioligand exposure, the animalsare sacrificed and the relevant brain regions dissected (frontal cortexfor 5-HT2A and striatum for D2 receptors) and examined for their contentof radioactivity. The level of non-specific binding is determined byexamining a brain region known not to contain the receptor of interest(in this case the cerebellum) or by administering an excess of compoundknown pharmacologically to interact with the receptor.

REFERENCES

[1644] Arnt, J. Acta Pharmacol. et Toxicol. 1982: 51, 321-329.

[1645] Berridge M. J., Downes P. C. , Hanley M. R. (1982) Lithiumamplifies agonist-dependent phosphotidyinositol response in brain andsalivary glands. Biochem. J., 206, 587-595.

[1646] Costall, B and Naylor, R J. Psychopharmacology. 1975: 43, 69-74.

[1647] Egan C. T., Herrick-Davis K., Miller K., Glennon R. A., andTeitler M. (1998) Agonist activity of LSD and lisuride at cloned 5-HT2Aand 5-HT2C receptors. Psychopharmacology, 136, 409-414.

[1648] Fitzgerald L W, Conklin D S, Krause C M, Marshall A P, PattersonJ P, Tran D P, Iyer G, Kostich W A, Largent B L, Hartig P R (1999)High-affinity agonist binding correlates with efficacy (intrinsicactivity) at the human serotonin 5-HT2A and 5-HT2C receptors: evidencefavoring the ternary complex and two-state models of agonist action. J.Neurochem., 72, 2127-2134.

[1649] Frost, J. J., Smith, A. C., Kuhar, M. J., Dannals, R. F., Wagner,H. N., 1987, In Vivo Binding of 3H-N-Methylspiperone to Dopamine andSerotonin Receptors. Life Sciences, 40:987-995.

[1650] Horlick, R. A., Sperle, K., Breth, L. A., Reid, C. C., Shen, E.S., Robbinds, A. K., Cooke, G. M., Largent, B. L. (1997) RapidGeneration of stable cell lines expressing corticotrophin-releasinghormone receptor for drug discovery. Protein Expr. Purif. 9, 301-308.

[1651] Lucki, I, Nobler, M. S., Frazer, A., 1984, Differential actionsof serotonin antagonists on two behavioral models of serotonin receptoractivation in the rat. J. Pharmacol. Exp. Ther. 228(1):133-139.

Dosage and Formulation

[1652] The serotonin agonist and serotonin antagonist compounds of thisinvention can be administered as treatment for the control or preventionof central nervous system disorders including obesity, anxiety,depression, psychosis, schizophrenia, sleep and sexual disorders,migraine and other conditions associated with cephalic pain, socialphobias, and gastrointestinal disorders such as dysfunction of thegastrointestinal tract motility by any means that produces contact ofthe active agent with the agent's site of action, i.e., 5-HT2 receptors,in the body of a mammal. It can be administered by any conventionalmeans available for use in conjunction with pharmaceuticals, either asan individual therapeutic agent or in a combination of therapeuticagents. It can be administered alone, but preferably is administeredwith a pharmaceutical carrier selected on the basis of the chosen routeof administration and standard pharmaceutical practice.

[1653] The compounds of the present invention can be administered insuch oral dosage forms as tablets, capsules (each of which includessustained release or timed release formulations), pills, powders,granules, elixirs, tinctures, suspensions, syrups, and emulsions.Likewise, they may also be administered in intravenous (bolus orinfusion), intraperitoneal, subcutaneous, or intramuscular form, allusing dosage forms well known to those of ordinary skill in thepharmaceutical arts.

[1654] The dosage administered will, of course, vary depending uponknown factors, such as the pharmacodynamic characteristics of theparticular agent and its mode and route of administration; the age,health and weight of the recipient; the nature and extent of thesymptoms; the kind of concurrent treatment; the frequency of treatment;and the effect desired. By way of general guidance, a daily dosage ofactive ingredient can be expected to be about 0.001 to about 1000milligrams per kilogram of body weight, with the preferred dose beingabout 0.01 to about 100 mg/kg; with the more preferred dose being about0.1 to about 30 mg/kg. Advantageously, compounds of the presentinvention may be administered in a single daily dose, or the total dailydosage may be administered in divided doses of two, three, or four timesdaily.

[1655] Dosage forms of compositions suitable for administration containfrom about 1 mg to about 100 mg of active ingredient per unit. In thesepharmaceutical compositions the active ingredient will ordinarily bepresent in an amount of about 0.5-95% by weight based on the totalweight of the composition. The active ingredient can be administeredorally in solid dosage forms, such as capsules, tablets and powders, orin liquid dosage forms, such as elixirs, syrups and suspensions. It canalso be administered parenterally, in sterile liquid dosage forms.

[1656] Gelatin capsules contain the active ingredient and powderedcarriers, such as lactose, starch, cellulose derivatives, magnesiumstearate, stearic acid, and the like. Similar diluents can be used tomake compressed tablets. Both tablets and capsules can be manufacturedas sustained release products to provide for continuous release ofmedication over a period of hours. Compressed tablets can be sugarcoated or film coated to mask any unpleasant taste and protect thetablet from the atmosphere, or enteric coated for selectivedisintegration in the gastrointestinal tract. Liquid dosage forms fororal administration can contain coloring and flavoring to increasepatient acceptance.

[1657] In general, water, a suitable oil, saline, aqueous dextrose(glucose), and related sugar solutions and glycols such as propyleneglycol or polyethylene glycols are suitable carriers for parenteralsolutions. Solutions for parenteral administration preferably contain awater soluble salt of the active ingredient, suitable stabilizingagents, and if necessary, buffer substances. Antioxidizing agents suchas sodium bisulfite, sodium sulfite, or ascorbic acid, either alone orcombined, are suitable stabilizing agents. Also used are citric acid andits salts, and sodium EDTA. In addition, parenteral solutions cancontain preservatives, such as benzalkonium chloride, methyl- orpropyl-paraben and chlorobutanol. Suitable pharmaceutical carriers aredescribed in Remington's Pharmaceutical Sciences, supra, a standardreference text in this field.

[1658] Useful pharmaceutical dosage-forms for administration of thecompounds of this invention can be illustrated as follows:

[1659] Capsules

[1660] A large number of unit capsules can be prepared by fillingstandard two-piece hard gelatin capsules each with 100 mg of powderedactive ingredient, 150 mg of lactose, 50 mg of cellulose, and 6 mgmagnesium stearic.

[1661] Soft Gelatin Capsules

[1662] A mixture of active ingredient in a digestible oil such assoybean oil, cottonseed oil or olive oil can be prepared and injected bymeans of a positive displacement pump into gelatin to form soft gelatincapsules containing 100 mg of the active ingredient. The capsules shouldthen be washed and dried.

[1663] Tablets

[1664] A large number of tablets can be prepared by conventionalprocedures so that the dosage unit is 100 mg of active ingredient, 0.2mg of colloidal silicon dioxide, 5 milligrams of magnesium stearate, 275mg of microcrystalline cellulose, 11 mg of starch and 98.8 mg oflactose. Appropriate coatings may be applied to increase palatability ordelay absorption.

[1665] Suspension

[1666] An aqueous suspension can be prepared for oral administration sothat each 5 mL contain 25 mg of finely divided active ingredient, 200 mgof sodium carboxymethyl cellulose, 5 mg of sodium benzoate, 1.0 g ofsorbitol solution, U.S.P., and 0.025 mg of vanillin.

[1667] Injectable

[1668] A parenteral composition suitable for administration by injectioncan be prepared by stirring 1.5% by weight of active ingredient in 10%by volume propylene glycol and water. The solution is sterilized bycommonly used techniques.

1. A compound of formula (I):

or a stereoisomer or a pharmaceutically acceptable salt form thereof,wherein: R¹ is selected from H, C(═O)R², C(═O)OR², C₁₋₈ alkyl, C₂₋₈alkenyl, C₂₋₈ alkynyl, C₃₋₇ cycloalkyl, C₁₋₆ alkyl substituted with Z,C₂₋₆ alkenyl substituted with Z, C₂₋₆ alkynyl substituted with Z, C₃₋₆cycloalkyl substituted with Z, aryl substituted with Z, 5-6 memberedheterocyclic ring system containing at least one heteroatom selectedfrom the group consisting of N, O, and S, said heterocyclic ring systemsubstituted with Z; C₁₋₃ alkyl substituted with Y, C₂₋₃ alkenylsubstituted with Y, C₂₋₃ alkynyl substituted with Y, C₁₋₆ alkylsubstituted with 0-2 R², C₂₋₆ alkenyl substituted with 0-2 R², C₂₋₆alkynyl substituted with 0-2 R², aryl substituted with 0-2 R², and 5-6membered heterocyclic ring system containing at least one heteroatomselected from the group consisting of N, O, and S, said heterocyclicring system substituted with 0-2 R²; Y is selected from C₃₋₆ cycloalkylsubstituted with Z, aryl substituted with Z, 5-6 membered heterocyclicring system containing at least one heteroatom selected from the groupconsisting of N, O, and S, said heterocyclic ring system substitutedwith Z; C₃-6 cycloalkyl substituted with —(C₁₋₃ alkyl)—Z, arylsubstituted with —(C₁₋₃ alkyl)-Z, and 5-6 membered heterocyclic ringsystem containing at least one heteroatom selected from the groupconsisting of N, O, and S, said heterocyclic ring system substitutedwith —(C₁₋₃ alkyl)-Z; Z is selected from H, —CH(OH)R²,—C(ethylenedioxy)R², —OR², —SR², —NR²R³, —C(O) R², —C(O)NR²R³,—NR³C(O)R², —C(O)OR², —OC(O)R², —CH(═NR⁴)NR²R³, —NHC(═NR⁴)NR²R³,—S(O)R², —S(O)₂R², —S(O)₂NR²R³, and —NR³S(O)₂R²; R², at each occurrence,is independently selected from halo, C₁₋₃ haloalkyl, C₁₋₄ alkyl, C₂₋₄alkenyl, C₂₋₄ alkynyl, C₃₋₆ cycloalkyl, aryl substituted with 0-5 R⁴²;C₃₋₁₀ carbocyclic residue substituted with 0-3 R⁴¹, and 5-10 memberedheterocyclic ring system containing from 1-4 heteroatoms selected fromthe group consisting of N, O, and S substituted with 0-3 R⁴¹; R³, ateach occurrence, is independently selected from H, C₁₋₄ alkyl, C₂₋₄alkenyl, C₂₋₄ alkynyl, and C₁₋₄ alkoxy; alternatively, R² and R³ join toform a 5- or 6-membered ring optionally substituted with —O— or —N(R⁴)—;R^(4,) at each occurrence, is independently selected from H and C₁₋₄alkyl; R^(4a) is H or C₁₋₄ alkyl; R^(4b) is H; alternatively, R^(4a) andR^(4b) are taken together to form ═O or ═S; R⁵ is H or C₁₋₄ alkyl; R⁶ isH or C₁₋₄ alkyl; alternatively, R⁵ and R⁶ are taken together to form afused heterocyclic ring of formula:

wherein: X is a bond, —CH₂—, —O—, —S—, —S(═O)—, —S(═O)₂—, —NR¹⁰—,—CH₂CH₂—, —OCH₂—, —SCH₂—, —CH₂O—, —CH₂S—, —CH₂NR¹⁰—, —NR¹⁰CH₂—,—NHC(═O)—, or —C(═O)NH—; and n is 1 or 2; R⁷ and R⁹, at each occurrence,are independently selected from H, halo, —CF₃, —OCF₃, —OH, —CN, —NO₂,—NR⁴⁶R⁴⁷, C₁₋₈ alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, C₁₋₄ haloalkyl, C₁₋₈alkoxy, (C₁₋₄ haloalkyl)oxy, C₃₋₁₀ cycloalkyl substituted with 0-2 R³³,C₁₋₄ alkyl substituted with 0-2 R¹¹, C₃₋₁₀ carbocyclic residuesubstituted with 0-3 R³³, aryl substituted with 0-5 R³³, 5-10 memberedheterocyclic ring system containing from 1-4 heteroatoms selected fromthe group consisting of N, O, and S substituted with 0-3 R³¹; OR¹²,SR¹², NR¹²R¹³, C(O)H, C(O)R¹², C(O)NR¹²R¹³, NR¹⁴C(O)R¹², C(O)OR¹²,OC(O)R¹², OC(O)OR¹², CH(═NR¹⁴)NR¹²R¹³, NHC(═NR¹⁴)NR¹²R¹³, S(O)R¹²,S(O)₂R¹², S(O)NR¹²R¹³, S(O)₂NR¹²R¹³, NR¹⁴S(O)R¹², NR¹⁴S (O)₂R¹²,NR¹²C(O)R¹⁵, NR¹²C(O)OR¹⁵, NR¹²S(O)₂R¹, and NR¹²C (O) NHR¹⁵; R⁸ isselected from H, halo, —CF₃, —OCF₃, —OH, —CN, —NO₂, C₁₋₈ alkyl, C₂₋₈alkenyl, C₂₋₈ alkynyl, C₁₋₄ haloalkyl, C₁₋₈ alkoxy, (C₁₋₄ haloalkyl)oxy,C₃₋₁₀ cycloalkyl substituted with 0-2 R³³, C₁₋₄ alkyl substituted with0-2 R¹¹, C₂₋₄ alkenyl substituted with 0-2 R¹¹, C₂₋₄ alkynyl substitutedwith 0-1 R¹¹, C₃₋₁₀ carbocyclic residue substituted with 0-3 R³³, arylsubstituted with 0-5 R³³, 5-10 membered heterocyclic ring systemcontaining from 1-4 heteroatoms selected from the group consisting of N,O, and S substituted with 0-3 R³¹; OR¹², SR¹², NR¹²R^(13,) C(O)H,C(O)R¹², C(O)NR¹²R¹³, NR¹⁴C(O)R¹², C(O)OR¹², OC(O)R¹², OC(O)OR¹²,CH(═NR¹⁴)NR¹²R¹³, NHC(═NR¹⁴)NR¹²R¹³, S(O)R¹², S(O)₂R¹², S(O)NR¹²R¹³,S(O)₂NR¹²R¹³, NR¹⁴S(O)R¹², NR¹⁴S(O)₂R¹², NR¹²C(O)R¹⁵, NR¹²C(O)OR¹⁵,NR¹²S(O)₂R¹⁵, and NR¹²C(O)NHR¹⁵; R¹⁰ is selected from H, C₁₋₄ alkylsubstituted with 0-2 R^(10A), C₂₋₄ alkenyl substituted with 0-2 R^(10A),C₂₋₄ alkynyl substituted with 0-1 R^(10A), and C₁₋₄ alkoxy; R^(10A) isselected from C₁₋₄ alkoxy, C₃₋₆ carbocyclic residue substituted with 0-3R³³, phenyl substituted with 0-3 R³³, and 5-6 membered heterocyclic ringsystem containing 1, 2, or 3 heteroatoms selected from the groupconsisting of N, O, and S; substituted with 0-2 R⁴⁴; R¹¹ is selectedfrom H, halo, —CF₃, —CN, —NO₂, C₁₋₈ alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl,C₁₋₄ haloalkyl, C₁₋₈ alkoxy, C₃₋₁₀ cycloalkyl, C₃₋₁₀ carbocyclic residuesubstituted with 0-3 R³³, aryl substituted with 0-5 R³³, 5-10 memberedheterocyclic ring system containing from 1-4 heteroatoms selected fromthe group consisting of N, O, and S substituted with 0-3 R³¹; OR¹²,SR¹², NR¹²R¹³, C(O)H, C(O)R¹², C(O)NR¹²R¹³, NR¹⁴C(O)R¹², C(O)OR¹²,OC(O)R¹², OC(O)OR¹², CH(═NR¹⁴)NR¹²R¹³, NHC(═NR¹⁴)NR¹²R¹³, S(O)R¹²,S(O)₂R¹², S(O)NR¹²R¹³, S(O)₂NR¹²R¹³, NR¹⁴S (O)R^(12,) NR¹⁴S (O)₂R¹²,NR¹²C(O)R¹⁵, NR¹²C(O)OR¹⁵, NR¹²S(O)₂R¹⁵, and NR¹²C (O) NHR¹⁵; R¹², ateach occurrence, is independently selected from C₁₋₄ alkyl substitutedwith 0-1 R^(12a), C₂₋₄ alkenyl substituted with 0-1 R^(12a), C₂₋₄alkynyl substituted with 0-1 R^(12a), C₃₋₆ cycloalkyl substituted with0-3 R³³, aryl substituted with 0-5 R³³; C₃₋₁₀ carbocyclic residuesubstituted with 0-3 R³³, and 5-10 membered heterocyclic ring systemcontaining from 1-4 heteroatoms selected from the group consisting of N,O, and S substituted with 0-3 R³¹; R^(12a), at each occurrence, isindependently selected from phenyl substituted with 0-5 R³³; C₃₋₁₀carbocyclic residue substituted with 0-3 R³³, and 5-10 memberedheterocyclic ring system containing from 1-4 heteroatoms selected fromthe group consisting of N, O, and S substituted with 0-3 R³¹; R¹³, ateach occurrence, is independently selected from H, C₁₋₄ alkyl, C₂₋₄alkenyl, and C₂₋₄ alkynyl; alternatively, R¹² and R¹³ join to form a 5-or 6-membered ring optionally substituted with —O— or —N(R¹⁴)—;alternatively, R¹² and R¹³ when attached to N may be combined to form a9- or 10-membered bicyclic heterocyclic ring system containing from 1-3heteroatoms selected from the group consisting of N, O, and S, whereinsaid bicyclic heterocyclic ring system is unsaturated or partiallysaturated, wherein said bicyclic heterocyclic ring system is substitutedwith 0-3 R¹⁶; R¹⁴, at each occurrence, is independently selected from Hand C₁₋₄ alkyl; R¹⁵, at each occurrence, is independently selected fromH, C₁₋₄ alkyl, C₂₋₄ alkenyl, and C₂₋₄ alkynyl; R¹⁶, at each occurrence,is independently selected from H, OH, halo, CN, NO₂, CF₃, SO₂R⁴⁵,NR⁴⁶R⁴⁷, —C(═O)H, C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, C₁₋₄haloalkyl, C₁₋₃ haloalkyl-oxy-, and C₁₋₃ alkyloxy-; R³¹, at eachoccurrence, is independently selected from H, OH, halo, CF₃, SO₂R⁴⁵,NR⁴⁶R⁴⁷, and C₁₋₄ alkyl; R³³, at each occurrence, is independentlyselected from H, OH, halo, CN, NO₂, CF₃, SO₂R⁴⁵, NR⁴⁶R⁴⁷, —C(═O)H,phenyl, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₆ cycloalkyl, C₁₋₄haloalkyl, C₁₋₄ haloalkyl-oxy-, C₁₋₄ alkyloxy-, C₁₋₄ alkylthio-, C₁₋₄alkyl—C(═O)—, C₁₋₄ alkyl—C(═O)NH—, C₁₋₄ alkyl-OC(═O)—, C₁₋₄alkyl—C(═O)O—, C₃₋₆ cycloalkyl-oxy-, C₃₋₆ cycloalkylmethyl-oxy-; C₁₋₆alkyl substituted with OH, methoxy, ethoxy, propoxy, butoxy, —SO₂R⁴⁵,—NR⁴⁶R⁴⁷, NR⁴⁶R⁴⁷C(═O)—, or (C₁₋₄ alkyl)CO₂—; and C₂₋₆ alkenylsubstituted with OH, methoxy, ethoxy, propoxy, butoxy, —SO₂R⁴⁵,—NR⁴⁶R⁴⁷, NR⁴⁶R⁴⁷C(═O)—, or (C₁₋₄ alkyl)CO₂—; R⁴¹, at each occurrence,is independently selected from H, CF₃, halo, OH, CO₂H, SO₂R⁴⁵, NR⁴⁶R⁴⁷,NO₂, CN, ═O; C₂₋₈ alkenyl, C₂₋₈ alkynyl, C₁₋₄ alkoxy, C₁₋₄ haloalkylC₁₋₄ alkyl substituted with 0-1 R⁴³, aryl substituted with 0-3 R⁴², and5-10 membered heterocyclic ring system containing from 1-4 heteroatomsselected from the group consisting of N, O, and S substituted with 0-3R⁴⁴; R⁴², at each occurrence, is independently selected from H, CF₃,halo, OH, CO₂H, SO₂R⁴⁵, SOR⁴⁵, SR⁴⁵, NR⁴⁶SO₂R⁴⁵, NR⁴⁶COR⁴⁵, NR⁴⁶R⁴⁷,NO₂, CN, CH(═NH)NH₂, NHC(═NH)NH₂, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₄alkoxy, C₁₋₄ haloalkyl, C₃₋₆ cycloalkyl, C₁₋₄ alkyl substituted with 0-1R⁴³, aryl substituted with 0-3 R⁴⁴ and 5-10 membered heterocyclic ringsystem containing from 1-4 heteroatoms selected from the groupconsisting of N, O, and S substituted with 0-3 R⁴⁴; R⁴³ is C₃₋₆cycloalkyl or aryl substituted with 0-3 R⁴⁴; R⁴⁴, at each occurrence, isindependently selected from H, halo, —OH, NR⁴⁶R⁴⁷, CO₂H, SO₂R⁴⁵, —CF₃,—OCF₃, —CN, —NO₂, C₁₋₄ alkyl, and C₁₋₄ alkoxy; R⁴⁵ is C₁₋₄ alkyl; R⁴⁶,at each occurrence, is independently selected from H and C₁₋₄ alkyl; andR⁴⁷, at each occurrence, is independently selected from H, C₁₋₄ alkyl,—C(═O)NH(C₁₋₄ alkyl), —SO₂(C₁₋₄ alkyl), —C(═O)O(C₁₋₄ alkyl), —C(═O) (C₁₋₄ alkyl), and —C(═O)H; provided when R⁵ is H or C₁₋₄ alkyl; and R⁶ isH or C₁₋₄ alkyl; then at least one of R⁷, R⁸ and R⁹ must be either 1) anaryl group substituted with 1-5 R³³; 2) an arylmethyl-group substitutedwith 1-5 R³³; or 3) —NR¹²R¹³ wherein R¹² is an aryl group substitutedwith 1-5 R³³.
 2. A compound of claim 1 of formula (I), wherein: R¹ isselected from H, C (=O) R², C (=O) OR², C₁₋₈ alkyl, C₂₋₈ alkenyl, C₂₋₈alkynyl, C₃₋₇ cycloalkyl, C₁₋₆ alkyl substituted with 0-2 R², C₂₋₆alkenyl substituted with 0-2 R², C₂₋₆ alkynyl substituted with 0-2 R²,aryl substituted with 0-2 R², and 5-6 membered heterocyclic ring systemcontaining at least one heteroatom selected from the group consisting ofN, O, and S, said heterocyclic ring system substituted with 0-2 R²; R²,at each occurrence, is independently selected from F, Cl, CH₂F, CHF₂,CF₃, C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, C₃₋₆ cycloalkyl, phenylsubstituted with 0-5 R⁴²; C₃₋₁₀ carbocyclic residue substituted with 0-3R⁴¹, and 5-10 membered heterocyclic ring system containing from 1-4heteroatoms selected from the group consisting of N, O, and Ssubstituted with 0-3 R⁴¹; R^(4a) is H or C₁₋₄ alkyl; R^(4b) is H;alternatively, R^(4a) and R^(4b) are taken together to form ═O or ═S; R⁵is H or C₁₋₄ alkyl; R⁶ is H or C₁₋₄ alkyl; R⁷ is selected from H, F, Cl,—CF₃, —OCF₃, —OH, —CN, —NO₂, NR¹²R¹³, C₁₋₈ alkyl, C₂₋₈ alkenyl, C₂₋₈alkynyl, C₁₋₄ haloalkyl, C₁₋₈ alkoxy, (C₁₋₄ haloalkyl)oxy, methylsubstituted with R¹¹; C₃₋₆ carbocyclic residue substituted with 0-3 R³³;and aryl substituted with 0-5 R³³; R⁸ is selected from H, F, Cl —CF₃,—OCF₃, —OH, —CN, —NO₂, NR¹²R¹³, C₁₋₈ alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl,C₁₋₄ haloalkyl, C₁₋₈ alkoxy, (C₁₋₄ haloalkyl)oxy, methyl substitutedwith R¹¹; C₃₋₆ carbocyclic residue substituted with 0-3 R³³; and arylsubstituted with 0-5 R³³; R⁹ is selected from H, F, Cl, —CF₃, —OCF₃,—OH, —CN, —NO₂, C₁₋₈ alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, C₁₋₄ haloalkyl,C₁₋₈ alkoxy, and (C₁₋₄ haloalkyl)oxy; R¹¹ is aryl substituted with 0-5R³³, R¹² is aryl substituted with 0-5 R³³, R¹³, at each occurrence, isindependently selected from H, C₁₋₄ alkyl, C₂₋₄ alkenyl, and C₂₋₄alkynyl; alternatively, R¹² and R¹³ join to form a 5- or 6-membered ringoptionally substituted with —O— or —N(R¹⁴)—; alternatively, R¹² and R¹³when attached to N may be combined to form a 9- or 10-membered bicyclicheterocyclic ring system containing from 1-3 heteroatoms selected fromthe group consisting of N, O, and S, wherein said bicyclic heterocyclicring system is unsaturated or partially saturated, wherein said bicyclicheterocyclic ring system is substituted with 0-3 R¹⁶; R¹⁴, at eachoccurrence, is independently selected from H and C₁₋₄ alkyl; R¹⁶, ateach occurrence, is independently selected from H, OH, halo, CN, NO₂,CF₃, SO₂R⁴⁵, NR⁴⁶R⁴⁷, —C(═O)H, C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl,C₁₋₄ haloalkyl, C₁₋₃ haloalkyl-oxy-, and C₁₋₃ alkyloxy-; R^(33,) at eachoccurrence, is independently selected from H, OH, halo, CN, NO_(2,) CF₃,SO₂R⁴⁵, NR⁴⁶R⁴⁷, —C(═O)H, phenyl, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₃₋₆ cycloalkyl, C₁₋₄ haloalkyl, C₁₋₄ haloalkyl-oxy-, C₁₋₄alkyloxy-, C₁₋₄ alkylthio-, C₁₋₄ alkyl—C(═O)—, C₁₋₄ alkyl—C(═O)NH—, C₁₋₄alkyl—OC(═O)—, C₁₋₄ alkyl—C(═O)O—, C₃₋₆ cycloalkyl-oxy-, C₃₋₆cycloalkylmethyl-oxy-; C₁₋₆ alkyl substituted with OH, methoxy, ethoxy,propoxy, butoxy, —SO₂R⁴⁵, —NR⁴⁶R⁴⁷, NR⁴⁶R⁴⁷C(═O)—, or (C₁₋₄ alkyl)CO₂—;and C₂₋₆ alkenyl substituted with OH, methoxy, ethoxy, propoxy, butoxy,—SO₂R⁴⁵, —NR⁴⁶R⁴⁷, NR⁴⁶R⁴⁷C(═O)—, or (C₁₋₄ alkyl)CO₂—; R⁴¹, at eachoccurrence, is independently selected from H, CF₃, halo, OH, CO₂H,SO₂R⁴⁵, NR⁴⁶R⁴⁷, NO₂, CN, ═O; C₂₋₈ alkenyl, C₂₋₈ alkynyl, C₁₋₄ alkoxy,C₁₋₄ haloalkyl C₁₋₄ alkyl substituted with 0-1 R⁴³, aryl substitutedwith 0-3 R⁴², and 5-10 membered heterocyclic ring system containing from1-4 heteroatoms selected from the group consisting of N, O, and Ssubstituted with 0-3 R⁴⁴; R⁴², at each occurrence, is independentlyselected from H, CF₃, halo, OH, CO₂H, SO₂R⁴⁵, SOR⁴⁵, SR⁴⁵, NR⁴⁶SO₂R⁴⁵,NR⁴⁶COR⁴⁵, NR⁴⁶R⁴⁷, NO₂, CN, CH(═NH)NH₂, NHC(═NH) NH₂, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₁₋₄ alkoxy, C₁₋₄ haloalkyl, C₃₋₆ cycloalkyl, C₁₋₄ alkylsubstituted with 0-1 R⁴³, aryl substituted with 0-3 R⁴⁴, and 5-10membered heterocyclic ring system containing from 1-4 heteroatomsselected from the group consisting of N, O, and S substituted with 0-3R⁴⁴; R⁴³ is C₃₋₆ cycloalkyl or aryl substituted with 0-3 R^(44;) R^(44,)at each occurrence, is independently selected from H, halo, —OH,NR⁴⁶R⁴⁷, CO₂H, SO₂R₄₅, —CF₃, —OCF₃, —CN, —NO₂, C₁₋₄ alkyl, and C₁₋₄alkoxy; R⁴⁵ is C₁₋₄ alkyl; R⁴⁶, at each occurrence, is independentlyselected from H and C₁₋₄ alkyl; and R⁴⁷, at each occurrence, isindependently selected from H, C₁₋₄alkyl, —C(═O)NH(C₁₋₄ alkyl),—SO₂(C₁₋₄ alkyl), —C(═O)O(C₁₋₄ alkyl), —C(═O)( C₁₋₄ alkyl), and —C(═O)H;provided at least one of R⁷ or R⁸ must be either 1) an aryl groupsubstituted with 1-5 R^(33; 2)) an arylmethyl- group substituted with1-5 R^(33;) or 3) —NR¹²R¹³ wherein R¹² is an aryl group substituted with1-5 R³³.
 3. A compound of claim 2 of formula (I), wherein: R¹ isselected from H, C₁₋₅ alkyl substituted with 0-1 R², C₂₋₅ alkenylsubstituted with 0-1 R², and C₂₋₃ alkynyl substituted with 0-1 R²; R² isC₃₋₆ cycloalkyl; R^(4a) is H; R^(4b) is H; R⁷ is selected from H, F, Cl,—CH₃, —OCH₃, —CF₃, —OCF₃, —CN, —NO₂, NR¹²R¹³, R¹¹; methyl substitutedwith R¹¹; and phenyl substituted with 0-2 R³³; R⁸ is selected from H, F,Cl, —CH₃, —OCH₃, —CF₃, —OCF₃, —CN, —NO₂, NR¹²R¹³, R¹¹; methylsubstituted with R¹¹; and phenyl substituted with 0-2 R³³; R⁹ isselected from H, F, Cl, —CH₃, —OCH₃, —CF₃, —OCF₃, —CN, and —NO₂; R¹¹ isselected from phenyl- substituted with 0-5 fluoro; naphthyl- substitutedwith 0-3 R³³; 2-(H₃CCH₂C(═O))-phenyl- substituted with R³³;2-(H₃CC(═O))-phenyl- substituted with R³³; 2-(HC(═O))-phenyl-substituted with R³³; 2-(H₃CCH(OH))-phenyl- substituted with R³³;2-(H₃CCH₂CH(OH))-phenyl- substituted with R³³; 2-(HOCH₂)-phenyl-substituted with R³³; 2-(HOCH₂CH₂)-phenyl- substituted with R³³;2-(H₃COCH₂)-phenyl- substituted with R³³; 2-(H₃COCH₂CH₂)-phenyl-substituted with R³³; 2-(H₃CCH(OMe))-phenyl- substituted with R³³;2-(H₃COC(═O))-phenyl- substituted with R³³; 2-(HOCH₂CH═CH)-phenyl-substituted with R³³; 2-((MeOC═O)CH═CH)-phenyl- substituted with R³³;2-(methyl)-phenyl- substituted with R³³; 2-(ethyl)-phenyl- substitutedwith R³³; 2-(i-propyl)-phenyl- substituted with R³³; 2-(F₃C)-phenyl-substituted with R³³; 2-(NC)-phenyl- substituted with R³³;2-(H₃CO)-phenyl- substituted with R³³; 2-(fluoro)-phenyl- substitutedwith R³³; 2-(chloro)-phenyl- substituted with R³³; 3-(NC)-phenyl-substituted with R³³; 3-(H₃CO)-phenyl- substituted with R³³;3-(fluoro)-phenyl- substituted with R³³; 3-(chloro)-phenyl- substitutedwith R³³; 4-(NC)-phenyl- substituted with R³³; 4-(fluoro)-phenyl-substituted with R³³; 4-(chloro)-phenyl- substituted with R³³;4-(H₃CS)-phenyl- substituted with R³³; 4-(H₃CO)-phenyl- substituted withR³³; 4-(ethoxy)-phenyl- substituted with R³³; 4-(i-propoxy)-phenyl-substituted with R³³; 4-(i-butoxy)-phenyl- substituted with R³³;4-(H₃CCH₂CH₂C(═O)) -phenyl- substituted with R³³; 4-((H₃C)₂CHC(═O))-phenyl- substituted with R³³; 4-(H₃CCH₂C(═O))-phenyl- substituted withR³³; 4-(H₃CC(═O))-phenyl- substituted with R³³;4-(H₃CCH₂CH₂CH(OH))-phenyl- substituted with R³³;4-((H₃C)₂CHCH(OH))-phenyl- substituted with R³³; 4-(H₃CCH₂CH(OH))-phenyl- substituted with R³³; 4-(H₃CCH(OH))-phenyl- substitutedwith R³³; 4-(cyclopropyloxy)-phenyl- substituted with R³³;4-(cyclobutyloxy)-phenyl- substituted with R³³; and4-(cyclopentyloxy)-phenyl- substituted with R³³; R¹² is selected fromphenyl- substituted with 0-5 fluoro; naphthyl- substituted with 0-3 R³³;2-(H₃CCH₂C(═O))-phenyl- substituted with R³³; 2-(H₃CC(═O))-phenyl-substituted with R³³; 2-(HC(═O))-phenyl- substituted with R³³;2-(H₃CCH(OH))-phenyl- substituted with R³³; 2-(H₃CCH₂CH(OH))-phenyl-substituted with R³³; 2-(HOCH₂)-phenyl- substituted with R³³;2-(HOCH₂CH₂)-phenyl- substituted with R³³; 2-(H₃COCH₂)-phenyl-substituted with R³³; 2-(H₃COCH₂CH₂) -phenyl- substituted with R³³;2-(H₃CCH(OMe))-phenyl- substituted with R³³; 2-(H₃COC(═O))-phenyl-substituted with R³³; 2-(HOCH₂CH═CH)-phenyl- substituted with R³³;2-((MeOC═O)CH═CH)-phenyl- substituted with R³³; 2-(methyl)-phenyl-substituted with R³³; 2-(ethyl)-phenyl- substituted with R³³;2-(i-propyl)-phenyl- substituted with R³³; 2-(F₃C)-phenyl- substitutedwith R³³; 2-(NC)-phenyl- substituted with R³³; 2-(H₃CO)-phenyl-substituted with R³³; 2-(fluoro)-phenyl- substituted with R³³;2-(chloro)-phenyl- substituted with R³³; 3-(NC)-phenyl- substituted withR³³; 3-(H₃CO)-phenyl- substituted with R³³; 3-(fluoro)-phenyl-substituted with R³³; 3-(chloro)-phenyl- substituted with R³³;4-(NC)-phenyl- substituted with R³³; 4-(fluoro)-phenyl- substituted withR³³; 4-(chloro)-phenyl- substituted with R³³; 4-(H₃CS)-phenyl-substituted with R³³; 4-(H₃CO)-phenyl- substituted with R³³;4-(ethoxy)-phenyl- substituted with R³³; 4-(i-propoxy)-phenyl-substituted with R³³; 4-(i-butoxy)-phenyl- substituted with R³³;4-(H₃CCH₂CH₂C(═O))-phenyl- substituted with R³³; 4-((H₃C)₂CHC(═O))-phenyl- substituted with R³³; 4-(H₃CCH₂C(═O)) -phenyl- substituted withR³³; 4-(H₃CC(═O))-phenyl- substituted with R³³;4-(H₃CCH₂CH₂CH(OH))-phenyl- substituted with R³³; 4-((H₃C)₂CHCH(OH))-phenyl- substituted with R³³; 4-(H₃CCH₂CH(OH))-phenyl- substituted withR³³; 4-(H₃CCH(OH))-phenyl- substituted with R³³;4-(cyclopropyloxy)-phenyl- substituted with R³³;4-(cyclobutyloxy)-phenyl- substituted with R³³; and4-(cyclopentyloxy)-phenyl- substituted with R³³; R¹³ is H, methyl, orethyl; alternatively, R¹² and R¹³ join to form a 5- or 6-membered ringselected from pyrrolyl, pyrrolidinyl, imidazolyl, piperidinyl,piperizinyl, methylpiperizinyl,and morpholinyl; alternatively, R¹² andR¹³ when attached to N may be combined to form a 9- or 10-memberedbicyclic heterocyclic ring system containing from 1-3 heteroatomsselected from the group consisting of N, O, and S; wherein said bicyclicheterocyclic ring system is selected from indolyl, indolinyl, indazolyl,benzimidazolyl, benzimidazolinyl, and benztriazolyl; wherein saidbicyclic heterocyclic ring system is substituted with 0-1 R¹⁶; R¹⁵ is H,methyl, ethyl, propyl, or butyl; R¹⁶, at each occurrence, isindependently selected from H, OH, F, Cl, CN, NO₂, methyl, ethyl,methoxy, ethoxy, trifluoromethyl, and trifluoromethoxy; and R³³, at eachoccurrence, is independently selected from H, F, Cl, —CH₃, —OCH₃, —CF₃,—OCF₃, —CN, and —NO₂. provided at least one of R⁷ or R⁸ must beeither 1) an aryl group substituted with 1-5 R³³; 2) an arylmethyl-group substituted with 1-5 R³³; or 3) —NR¹²R¹³ wherein R¹² is an arylgroup substituted with 1-5 R³³.
 4. A compound of claim 2 of Formula (I)wherein: R¹ is selected from hydrogen, methyl, ethyl, n-propyl, n-butyl,s-butyl, t-butyl, n-pentyl, n-hexyl, 2-propyl, 2-butyl, 2-pentyl,2-hexyl, 2-methylpropyl, 2-methylbutyl, 2-methylpentyl, 2-ethylbutyl,3-methylpentyl, 3-methylbutyl, 4-methylpentyl, 2-fluoroethyl,2,2-difluoroethyl, 2,2,2-trifluoroethyl, 2-propenyl,2-methyl-2-propenyl, trans-2-butenyl, 3-methyl-butenyl, 3-butenyl,trans-2-pentenyl, cis-2-pentenyl, 4-pentenyl, 4-methyl-3-pentenyl,3,3-dichloro-2-propenyl, trans-3-phenyl-2-propenyl, cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, cyclopropylmethyl,cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, —CH═CH₂,—CH₂—CH═CH₂, —CH═CH—CH₃, —C≡—CH, —C≡C—CH₃, and —CH₂—C≡—CH; R^(4a) is H;R^(4b) is H; alternatively, R^(4a) and R^(4b) are taken together to form═O; R⁷ is selected from hydrogen, fluoro, chloro, bromo, cyano, methyl,ethyl, propyl, isopropyl, butyl, t-butyl, nitro, trifluoromethyl,methoxy, ethoxy, isopropoxy, and trifluoromethoxy; R⁸ is selected from2-chlorophenyl, 2-fluorophenyl, 2-bromophenyl, 2-cyanophenyl,2-methylphenyl, 2-trifluoromethylphenyl, 2-methoxyphenyl,2-trifluoromethoxyphenyl, 3-chlorophenyl, 3-fluorophenyl, 3-bromophenyl,3-cyanophenyl, 3-methylphenyl, 3-ethylphenyl, 3-propylphenyl,3-isopropylphenyl, 3-butylphenyl, 3-trifluoromethylphenyl,3-methoxyphenyl, 3-isopropoxyphenyl, 3-trifluoromethoxyphenyl,3-thiomethoxyphenyl, 4-chlorophenyl, 4-fluorophenyl, 4-bromophenyl,4-cyanophenyl, 4-methylphenyl, 4-ethylphenyl, 4-propylphenyl,4-isopropylphenyl, 4-butylphenyl, 4-trifluoromethylphenyl,4-methoxyphenyl, 4-isopropoxyphenyl, 4-trifluoromethoxyphenyl,4-thiomethoxyphenyl, 2,3-dichlorophenyl, 2,3-difluorophenyl,2,3-dimethylphenyl, 2,3-ditrifluoromethylphenyl, 2,3-dimethoxyphenyl,2,3-ditrifluoromethoxyphenyl, 2,4-dichlorophenyl, 2,4-difluorophenyl,2,4-dimethylphenyl, 2,4-ditrifluoromethylphenyl, 2,4-dimethoxyphenyl,2,4-ditrifluoromethoxyphenyl, 2,5-dichlorophenyl, 2,5-difluorophenyl,2,5-dimethylphenyl, 2,5-ditrifluoromethylphenyl, 2,5-dimethoxyphenyl,2,5-ditrifluoromethoxyphenyl, 2,6-dichlorophenyl, 2,6-difluorophenyl,2,6-dimethylphenyl, 2,6-ditrifluoromethylphenyl, 2,6-dimethoxyphenyl,2,6-ditrifluoromethoxyphenyl, 3,4-dichlorophenyl, 3,4-difluorophenyl,3,4-dimethylphenyl, 3,4-ditrifluoromethylphenyl, 3,4-dimethoxyphenyl,3,4-ditrifluoromethoxyphenyl, 2,4,6-trichlorophenyl,2,4,6-trifluorophenyl, 2,4,6-trimethylphenyl,2,4,6-tritrfluoromethylphenyl, 2,4,6-trimethoxyphenyl,2,4,6-tritrifluoromethoxyphenyl, 2-chloro-4-CF₃-phenyl,2-fluoro-3-chloro-phenyl, 2-chloro-4-CF₃-phenyl,2-chloro-4-methoxy-phenyl, 2-methoxy-4-isopropyl-phenyl,2-CF₃-4-methoxy-phenyl, 2-methyl-4-methoxy-5-fluoro-phenyl,2-methyl-4-methoxy-phenyl, 2-chloro-4-CF₃O-phenyl,2,4,5-trimethyl-phenyl, 2-methyl-4-chloro-phenyl, 4-acetylphenyl,3-acetamidophenyl, 2-naphthyl; 2-Me-5-F-phenyl, 2-F-5-Me-phenyl,2-MeO-5-F-phenyl, 2-Me-3-Cl-phenyl, 3-NO₂-phenyl, 2-NO₂-phenyl,2-Cl-3-Me-phenyl, 2-Me-4-EtO-phenyl, 2-Me-4-F-phenyl, 2-Cl-6-F-phenyl,2-Cl-4-(CHF₂)O-phenyl, 2,4-diMeO-6-F-phenyl, 2-CF₃-6-F-phenyl,2-MeS-phenyl, 2,6-diCl-4-MeO-phenyl, 2,3,4-triF-phenyl,2,6-diF-4-Cl-phenyl, 2,3,4,6-tetraF-phenyl, 2,3,4,5,6-pentaF-phenyl,2-CF₃-4-EtO-phenyl, 2-CF₃-4-iPrO-phenyl, 2-CF₃-4-Cl-phenyl,2-CF₃-4-F-phenyl, 2-Cl-4-EtO-phenyl, 2-Cl-4-iPrO-phenyl,2-Et-4-MeO-phenyl, 2-CHO-4-MeO-phenyl, 2-CH₃CH(OH)-4-MeO-phenyl,2-CH₃CH(OH)-4-F-phenyl, 2-CH₃CH(OH)-4-Cl-phenyl,2-CH₃CH(OH)-4-Me-phenyl, 2-CH₃CH(OMe)-4-MeO-phenyl,2-CH₃C(═O)-4-MeO-phenyl, 2-CH₃C(═O)-4-F-phenyl, 2-CH₃C(═O)-4-Cl-phenyl,2-CH₃C(═O)-4-Me-phenyl, 2-H₂C(OH)-4-MeO-phenyl, 2-H₂C(OMe)-4-MeO-phenyl, 2-H₃CCH₂CH(OH)-4-MeO-phenyl, 2-H₃CCH₂C (═O)-4-MeO-phenyl,2-CH₃CO₂CH₂CH₂-4-MeO-phenyl, (Z)-2-HOCH₂CH═CH-4-MeO-phenyl,(E)-2-HOCH₂CH═CH-4-MeO-phenyl, (Z)-2-CH₃CO₂CH═CH-4-MeO-phenyl,(E)-2-CH₃CO₂CH═CH-4-MeO-phenyl, 2-CH₃OCH₂CH₂-4-MeO-phenyl,2-F-4-MeO-phenyl, 2-Cl-4-F-phenyl, cyclohexyl, cyclopentyl,cyclohexylmethyl, benzyl, 2-F-benzyl, 3-F-benzyl, 4-F-benzyl,3-MeO-benzyl, 3-OH-benzyl, 2-MeO-benzyl, 2-OH-benzyl,2-MeOC(═O)-3-MeO-phenyl , 2-Me-4-CN-phenyl, 2-Me-3-CN-phenyl,2-Me-4-MeS-phenyl, 2-CF₃-4-CN-phenyl, 2-CHO-phenyl, 3-CHO-phenyl,2-HOCH₂-phenyl, 3-HOCH₂-phenyl, 3-Me OCH₂-phenyl, 3-Me₂NCH₂-phenyl,3-CN-4-F-phenyl, 2-Me-4-H₂NCO-phenyl, 2-Me-4-MeOC(═O)-phenyl,3-H₂NCO-4-F-phenyl, 2-Me₂NCH₂-4-MeO-phenyl-, 2-Me-4-CH₃C(═O)-phenyl,phenyl—NH—, (1-naphthyl)-NH—, (2-naphthyl)-NH—, (2-[1,1′-biphenyl])-NH—,(3-[1,1′-biphenyl])-NH—, (4-[1,1′-biphenyl])-NH—, (2-F-phenyl)-NH—,(2-Cl-phenyl)-NH—, (2-CF₃-phenyl)-NH—, (2-CH₃-phenyl)-NH—,(2-OMe-phenyl)-NH—, (2-CN-phenyl)-NH—, (2-OCF₃-phenyl)-NH—,(2-SMe-phenyl)-NH—, (3-F-phenyl)-NH—, (3-Cl-phenyl)-NH—,(3-CF₃-phenyl)-NH—, (3-CH₃-phenyl)-NH—, (3-OMe-phenyl)-NH—,(3-CN-phenyl)-NH—, (3-OCF₃-phenyl)-NH—, (3-SMe-phenyl)-NH—,(4-F-phenyl)-NH—, (4-Cl-phenyl)-NH—, (4-CF₃-phenyl)-NH—,(4-CH₃-phenyl)-NH—, (4-OMe-phenyl)-NH—, (4-CN-phenyl)-NH—,(4-OCF₃-phenyl)-NH—, (4-SMe-phenyl)-NH—, (2,3-diCl-phenyl)-NH—,(2,4-diCl-phenyl )-NH—, (2,5-diCl-phenyl)-NH—, (2,6-diCl-phenyl)-NH—,(3,4-diCl-phenyl)-NH—, (3,5-diCl-phenyl)-NH—, (2,3-diF-phenyl)—NH—,(2,4-diF-phenyl)-NH—, (2,5-diF-phenyl)-NH—, (2,6-diF-phenyl)-NH—,(3,4-diF-phenyl)-NH—, (3,5-diF-phenyl)-NH—, (2,3-diCH₃-phenyl)-NH—,(2,4-diCH₃-phenyl)-NH—, (2,5-diCH₃-phenyl)-NH—, (2,6-diCH₃-phenyl)-NH—,(3,4-diCH₃-phenyl)-NH—, (3,5-diCH₃-phenyl)-NH—, (2,3-diCF₃-phenyl)-NH—,(2,4-diCF₃-phenyl)-NH—, (2,5-diCF₃-phenyl)-NH—, (2,6-diCF₃-phenyl)-NH—,(3,4-diCF₃-phenyl)-NH—, (3,5-diCF₃-phenyl)-NH−, (2,3-diOMe-phenyl)-NH—,(2,4-diOMe-phenyl)-NH—, (2,5-diOMe-phenyl)-NH—, (2,6-dioMe-phenyl)-NH—,(3,4-dioMe-phenyl)-NH—, (3,5-dioMe-phenyl)-NH—, (2-F-3-Cl-phenyl)-NH—,(2-F-4-Cl-phenyl)-NH—, (2-F-5-Cl-phenyl)-NH—, (2-F-6-Cl-phenyl)-NH—,(2-F-3-CH₃-phenyl)-NH—, (2-F-4-CH₃-phenyl)-NH—, (2-F-5-CH₃-phenyl)-NH—,(2-F-6-CH₃-phenyl)-NH—, (2-F-3-CF₃-phenyl)-NH—, (2-F-4-CF₃-phenyl)-NH—,(2-F-5-CF₃-phenyl)-NH—, (2-F-6-CF₃-phenyl)-NH—, (2-F-3-OMe-phenyl)-NH—,(2-F-4-OMe-phenyl)-NH—, (2-F-5-OMe-phenyl)-NH—, (2-F-6-OMe-phenyl)-NH—,(2-Cl-3-F-phenyl)-NH—, (2-Cl-4-F-phenyl)-NH—, (2-Cl-5-F-phenyl)-NH—,(2-Cl-6-F-phenyl)-NH—, (2-Cl-3-CH₃-phenyl)-NH—, (2-Cl-4-CH₃-phenyl)-NH—,(2-Cl-5-CH₃-phenyl)-NH—, (2-Cl-6-CH₃-phenyl)-NH—,(2-Cl-3-CF₃-phenyl)-NH—, (2-Cl-4-CF₃-phenyl)-NH—,(2-Cl-5-CF₃-phenyl)-NH—, (2-Cl-6-CF₃-phenyl)-NH—,(2-Cl-3-OMe-phenyl)-NH—, (2-Cl-4-OMe-phenyl)-NH—,(2-Cl-5-OMe-phenyl)-NH—, (2-Cl-6-OMe-phenyl)-NH—,(2-CH₃-3-F-phenyl)-NH—, (2-CH₃-4-F-phenyl)-NH—, (2-CH₃-5-F-phenyl)-NH—,(2-CH₃-6-F-phenyl)-NH—, (2-CH₃-3-Cl-phenyl)-NH—,(2-CH₃-4-Cl-phenyl)-NH—, (2-CH₃-5-Cl-phenyl)-NH—,(2-CH₃-6-Cl-phenyl)-NH—, (2-CH₃-3-CF₃-phenyl)-NH—,(2-CH₃-4-CF₃-phenyl)-NH—, (2-CH₃-5-CF₃-phenyl)-NH—,(2-CH₃-6-CF₃-phenyl)-NH—, (2-CH₃-3-OMe-phenyl)-NH—,(2-CH₃-4-OMe-phenyl)-NH—, (2-CH₃-5-OMe-phenyl)-NH—,(2-CH₃-6-OMe-phenyl)-NH—, (2-CF₃-3-F-phenyl)-NH—,(2-CF₃-4-F-phenyl)-NH—, (2-CF₃-5-F-phenyl)-NH—, (2-CF₃-6-F-phenyl)-NH—,(2-CF₃-3-Cl-phenyl)-NH—, (2-CF₃-4-Cl-phenyl)-NH—,(2-CF₃-5-Cl-phenyl)-NH—, (2-CF₃-6-Cl-phenyl)-NH—,(2-CF₃-3-CH₃-phenyl)-NH—, (2-CF₃-4-CH₃-phenyl)-NH—,(2-CH₃-5-CF₃-phenyl)-NH—, (2-CF₃-6-CH₃-phenyl)-NH—,(2-CF₃-3-OMe-phenyl)-NH—, (2-CF₃-4-OMe-phenyl)-NH—,(2-CF₃-5-OMe-phenyl)-NH—, (2-CF₃-6-OMe-phenyl)-NH—,(2-OMe-3-F-phenyl)-NH—, (2-OMe-4-F-phenyl)-NH—, (2-OMe-5-F-phenyl)-NH—,(2-OMe-6-F-phenyl)-NH—, (2-OMe-3-Cl-phenyl)-NH—,(2-OMe-4-Cl-phenyl)-NH—, (2-OMe-5-Cl-phenyl)-NH—,(2-OMe-6-Cl-phenyl)-NH—, (2-OMe-3-CH₃-phenyl)-NH—,(2-OMe-4-CH₃-phenyl)-NH—, (2-OMe-5-CH₃-phenyl)-NH—,(2-OMe-6-CH₃-phenyl)-NH—, (2-OMe-3-CF₃-phenyl)-NH—,(2-OMe-4-CF₃-phenyl)-NH—, (2-OMe-5-CF₃-phenyl)-NH—,(2-OMe-6-CF₃-phenyl)-NH— (3-CF₃-4-Cl-phenyl)-NH—,(3-CF₃-4-C(O)CH₃-phenyl)-NH—, (2,3,5-triCl-phenyl)-NH—,(3-CH₃-4-CO₂Me-phenyl)-NH—, and (3-CHO-4-OMe-phenyl)-NH—; and R⁹ isselected from hydrogen, fluoro, chloro, bromo, cyano, methyl, ethyl,propyl, isopropyl, butyl, t-butyl, nitro, trifluoromethyl, methoxy,ethoxy, isopropoxy, and trifluoromethoxy.
 5. A compound of claim 1 offormula (I-a)

wherein: X is a bond —CH₂—, —O—, —S—, —S(═O)—, —S(═O)₂—, —NR¹⁰—,—CH₂CH₂—, —OCH₂—, —SCH₂—, —CH₂O—, —CH₂S—, —NR¹⁰CH₂—, or —CH₂NR¹⁰—; n is1 or 2; R¹ is selected from H, C(═O)R², C(═O)OR², C₁₋₈ alkyl, C₂₋₈alkenyl, C₂₋₈ alkynyl, C₃₋₇ cycloalkyl, C₁₋₆ alkyl substituted with 0-2R², C₂₋₆ alkenyl substituted with 0-2 R², C₂₋₆ alkynyl substituted with0-2 R², aryl substituted with 0-2 R², and 5-6 membered heterocyclic ringsystem containing at least one heteroatom selected from the groupconsisting of N, O, and S, said heterocyclic ring system substitutedwith 0-2 R²; R², at each occurrence, is independently selected from F,Cl, CH₂F, CHF₂, CF₃, C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, C₃₋₆cycloalkyl, phenyl substituted with 0-5 R⁴²; C₃₋₁₀ carbocyclic residuesubstituted with 0-3 R⁴¹, and 5-10 membered heterocyclic ring systemcontaining from 1-4 heteroatoms selected from the group consisting of N,O, and S substituted with 0-3 R⁴¹; R^(4a) is H or C₁₋₄ alkyl; R^(4b) isH; alternatively, R^(4a) and R^(4b) are taken together to form ═O or ═S;R⁷ and R⁹, at each occurrence, are independently selected from H, halo,—CF₃, —OCF₃, —OH, —CN, —NO₂, —NR⁴⁶R⁴⁷, C₁₋₈ alkyl, C₂₋₈ alkenyl, C₂₋₈alkynyl, C₁₋₄ haloalkyl, C₁₋₈ alkoxy, (C₁₋₄ haloalkyl)oxy, C₃₋₁₀cycloalkyl substituted with 0-2 R³³, C₁₋₄ alkyl substituted with 0-2R¹¹, C₃₋₁₀ carbocyclic residue substituted with 0-3 R³³, arylsubstituted with 0-5 R³³, 5-10 membered heterocyclic ring systemcontaining from 1-4 heteroatoms selected from the group consisting of N,O, and S substituted with 0-3 R³¹; OR¹², SR¹², NR¹²R¹³, C(O)H, C(O)R¹²,C(O)NR¹²R¹³, NR¹⁴C(O)R¹², C(O)OR¹², OC(O)R¹², OC(O)OR¹²,CH(═NR¹⁴)NR¹²R¹³, NHC(═NR¹⁴)NR¹²R¹³, S(O)R¹², S(O)₂R¹², S(O)NR¹²R¹³,S(O)₂NR¹²R¹³, NR¹⁴S(O)R¹², NR¹⁴S (O)₂R¹², NR¹²C(O)R¹⁵, NR¹²C(O)OR¹⁵,NR¹²S(O)₂R¹⁵, and NR¹²C(O)NHR¹⁵; R⁸ is selected from H, halo, —CF₃,—OCF₃, —OH, —CN, —NO₂, C₁₋₈ alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, C₁₋₄haloalkyl, C₁₋₈ alkoxy, (C₁₋₄ haloalkyl)oxy, C₃₋₁₀ cycloalkylsubstituted with 0-2 R³³, C₁₋₄ alkyl substituted with 0-2 R¹¹, C₂₋₄alkenyl substituted with 0-2 R¹¹, C₂₋₄ alkynyl substituted with 0-1 R¹¹,C₃₋₁₀ carbocyclic residue substituted with 0-3 R³³, aryl substitutedwith 0-5 R³³, 5-10 membered heterocyclic ring system containing from 1-4heteroatoms selected from the group consisting of N, O, and Ssubstituted with 0-3 R³¹; OR¹², SR¹², NR¹²R¹³, C(O)H, C(O)R¹²,C(O)NR¹²R¹³, NR¹⁴C(O)R¹², C(O)OR¹²,OC(O)R¹², OC(O)R¹² ,CH(═NR¹⁴)NR¹²R¹³, NHC(═NR¹⁴)NR¹²R¹³, S(O)R₂R¹², S(O)NR¹²R¹³,S(O)₂NR¹²R¹³, NR¹⁴S(O)R¹², NR¹⁴S(O)₂R¹², NR¹²C(O)R¹⁵, NR¹²C(O)OR¹⁵,NR¹²S(O)₂R¹⁵, and NR¹²C(O)NHR¹⁵; R¹⁰ is selected from H, C₁₋₄ alkyl,C₂₋₄ alkenyl, C₂₋₄ alkynyl, and C₁₋₄ alkoxy; R¹¹ is selected from H,halo, —CF₃, —CN, —NO₂, C₁₋₈ alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, C₁₋₄haloalkyl, C₁₋₈ alkoxy, C₃₋₁₀ cycloalkyl, C₃₋₁₀ carbocyclic residuesubstituted with 0-3 R³³, aryl substituted with 0-5 R³³, 5-10 memberedheterocyclic ring system containing from 1-4 heteroatoms selected fromthe group consisting of N, O, and S substituted with 0-3 R³¹; OR¹²,SR¹², NR¹²R¹³, C(O)R¹², C(O)NR¹²R¹³, NR¹⁴C(O)R¹², C(O)OR¹², OC(O)R¹²,OC(O)OR¹², CH(═NR¹⁴)NR¹²R¹³, NHC(═NR¹⁴)NR¹²R¹³, S(O)R¹³, S(O)₂R¹²,S(O)NR¹²R¹³, S(O)₂NR¹²R¹³, NR¹⁴S(O)R¹², NR¹⁴S(O)₂R¹², NR¹²C(O)R¹⁵,NR¹²C(O)OR¹⁵, NR¹²S(O)₂R¹⁵, and NR¹²C(O)NHR¹⁵; R¹², at each occurrence,is independently selected from C₁₋₄ alkyl substituted with 0-1 R^(12a),C₂₋₄ alkenyl substituted with 0-1 R^(12a), C₂₋₄ alkynyl substituted with0-1 R^(12a), C₃₋₆ cycloalkyl substituted with 0-3 R³³, aryl substitutedwith 0-5 R³³; C₃₋₁₀ carbocyclic residue substituted with 0-3 R³³, and5-10 membered heterocyclic ring system containing from 1-4 heteroatomsselected from the group consisting of N, O, and S substituted with 0-3R³¹; R^(12a), at each occurrence, is independently selected from phenylsubstituted with 0-5 R³³; C₃₋₁₀ carbocyclic residue substituted with 0-3R³³, and 5-10 membered heterocyclic ring system containing from 1-4heteroatoms selected from the group consisting of N, O, and Ssubstituted with 0-3 R³¹; R¹³, at each occurrence, is independentlyselected from H, C₁₋₄ alkyl, C₂₋₄ alkenyl, and C₂₋₄ alkynyl;alternatively, R¹² and R¹³ join to form a 5- or 6-membered ringoptionally substituted with —O— or —N(R¹⁴)—; alternatively, R¹² and R¹³when attached to N may be combined to form a 9- or 10-membered bicyclicheterocyclic ring system containing from 1-3 heteroatoms selected fromthe group consisting of N, O, and S, wherein said bicyclic heterocyclicring system is unsaturated or partially saturated, wherein said bicyclicheterocyclic ring system is substituted with 0-3 R¹⁶; R¹⁴, at eachoccurrence, is independently selected from H and C₁₋₄ alkyl; R¹⁵, ateach occurrence, is independently selected from H, C₁₋₄ alkyl, C₂₋₄alkenyl, and C₂₋₄ alkynyl; R¹⁶, at each occurrence, is independentlyselected from H, OH, halo, CN, NO₂, CF₃, SO₂R⁴⁵, NR⁴⁶R⁴⁷, —C(═O)H, C₁₋₄alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, C₁₋₄ haloalkyl, C₁₋₃ haloalkyl-oxy-,and C₁₋₃ alkyloxy-; R³¹, at each occurrence, is independently selectedfrom H, OH, halo, CF₃, SO₂R⁴⁵, NR⁴⁶R⁴⁷, and C₁₋₄ alkyl; R³³, at eachoccurrence, is independently selected from H, OH, halo, CN, NO₂, CF₃,SO₂R⁴⁵, NR⁴⁶R⁴⁷, —C(═O)H, phenyl, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₃₋₆ cycloalkyl, C₁₋₄ haloalkyl, C₁₋₄ haloalkyl-oxy-, C₁₋₄alkyloxy-, C₁₋₄ alkylthio-, C₁₋₄ alkyl-C(═O)—, C₁₋₄ alkyl-C(═O)NH—, C₁₋₄alkyl-OC(═O)—, C₁₋₄ alkyl-C(═O)O—, C₃₋₆ cycloalkyl-oxy-, C₃₋₆cycloalkylmethyl-oxy-; C₁₋₆ alkyl substituted with OH, methoxy, ethoxy,propoxy, butoxy, —SO₂R⁴⁵, —NR⁴⁶R⁴⁷, NR⁴⁶R⁴⁷C(═O)—, or (C₁₋₄ alkyl)CO₂—;and C₂₋₆ alkenyl substituted with OH, methoxy, ethoxy, propoxy, butoxy,—SO₂R⁴⁵, —NR⁴⁶R⁴⁷, NR⁴⁶R⁴⁷C(═O)—, or (C₁₋₄ alkyl)CO₂—; R⁴¹, at eachoccurrence, is independently selected from H, CF₃, halo, OH, CO₂H,SO₂R⁴⁵, NR⁴⁶R⁴⁷, NO₂, CN; C₂₋₈ alkenyl, C₂₋₈ alkynyl, C₁₋₄ alkoxy, C₁₋₄haloalkyl C₁₋₄ alkyl substituted with 0-1 R⁴³, aryl substituted with 0-3R⁴², and 5-10 membered heterocyclic ring system containing from 1-4heteroatoms selected from the group consisting of N, O, and Ssubstituted with 0-3 R⁴⁴; R⁴², at each occurrence, is independentlyselected from H, CF₃, halo, OH, CO₂H, SO₂R⁴⁵, NR⁴⁶R⁴⁷, NO₂, CN,CH(═NH)NH₂, NHC(═NH)NH₂, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₄ alkoxy, C₁₋₄haloalkyl, C₃₋₆ cycloalkyl, C₁₋₄ alkyl substituted with 0-1 R⁴³, arylsubstituted with 0-3 R⁴⁴, and 5-10 membered heterocyclic ring systemcontaining from 1-4 heteroatoms selected from the group consisting of N,O, and S substituted with 0-3 R⁴⁴; R⁴³ is C₃₋₆ cycloalkyl or arylsubstituted with 0-3 R⁴⁴; R^(44,) at each occurrence, is independentlyselected from H, halo, —OH, NR⁴⁶R⁴⁷, CO₂H, SO₂R⁴⁵, —CF₃, —OCF₃, —CN,—NO₂, C₁₋₄ alkyl, and C₁₋₄ alkoxy; R⁴⁵ is C₁₋₄ alkyl; R⁴⁶, at eachoccurrence, is independently selected from H and C₁₋₄ alkyl; and R⁴⁷, ateach occurrence, is independently selected from H and C₁₋₄ alkyl.
 6. Acompound of claim 5 of formula (I-b)

wherein: X is —CH₂—, —O—, —S—, —CH₂CH₂—, —OCH₂—, —SCH₂—, —CH₂O—, or—CH₂S—; R¹ is selected from H, C(═O)R², C(═O)OR², C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₃₋₆ cycloalkyl, C₁₋₄ alkyl substituted with 0-2R², C₂₋₄ alkenyl substituted with 0-2 R², and C₂₋₄ alkynyl substitutedwith 0-2 R²; R², at each occurrence, is independently selected from C₁₋₄alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, C₃₋₆ cycloalkyl, phenyl substitutedwith 0-5 R⁴²; C₃₋₁₀ carbocyclic residue substituted with 0-3 R⁴¹, and5-10 membered heterocyclic ring system containing from 1-4 heteroatomsselected from the group consisting of N, O, and S substituted with 0-3R⁴¹; R^(4a) is H or C₁₋₄ alkyl; R^(4b) is H; alternatively, R^(4a) andR^(4b) are taken together to form ═O or ═S; R⁷ and R⁹, at eachoccurrence, are independently selected from H, halo, —CF₃, —OCF₃, —OH,—CN, —NO₂, —NR⁴⁶R⁴⁷, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆haloalkyl, C₁₋₆ alkoxy, (C₁₋₄ haloalkyl)oxy, C₃₋₁₀ cycloalkylsubstituted with 0-2 R³³, C₁₋₄ alkyl substituted with 0-2 R¹¹, C₃₋₁₀carbocyclic residue substituted with 0-3 R³³, aryl substituted with 0-5R³³, 5-10 membered heterocyclic ring system containing from 1-4heteroatoms selected from the group consisting of N, O, and Ssubstituted with 0-3 R³¹; OR¹², SR¹², NR¹²R¹³, C(O)H, C(O)R¹²,C(O)NR¹²R¹³, NR¹⁴C(O)R¹², C(O)OR¹², OC(O)R¹², OC(O)OR¹²,CH(═NR¹⁴)NR¹²R¹³, NHC(═NR¹⁴)NR¹²R¹³, S(O)R¹², S(O)₂R¹², S(O)NR¹²R¹³,S(O)₂NR¹²R¹³, NR¹⁴S(O)R¹², and NR¹⁴S(O)₂R¹²; R⁸ is selected from H,halo, —CF₃, —OCF₃, —OH, —CN, —NO₂, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₁₋₆ haloalkyl, C₁₋₆ alkoxy, (C₁₋₄ haloalkyl)oxy, C₃₋₁₀cycloalkyl substituted with 0-2 R³³, C₁₋₄ alkyl substituted with 0-2R¹¹, C₂₋₄ alkenyl substituted with 0-2 R¹¹, C₂₋₄ alkynyl substitutedwith 0-1 R¹¹, C₃₋₁₀ carbocyclic residue substituted with 0-3 R³³, arylsubstituted with 0-5 R³³, 5-10 membered heterocyclic ring systemcontaining from 1-4 heteroatoms selected from the group consisting of N,O, and S substituted with 0-3 R³¹; OR¹², SR¹² NR¹²R¹³, C(O)H,C(O)R^(12,) C(O)NR¹²R¹³, NR¹⁴C(O)R¹², C(O)OR¹², OC(O)R¹², OC(O)OR¹² ,CH(═NR¹⁴)NR¹²R¹³, NHC(═NR¹⁴)NR¹²R¹³, S(O)R¹², S(O)₂R¹², S(O)NR¹² R¹³,S(O)₂NR¹²R¹³, NR¹⁴S(O)R¹², NR¹⁴S(O)₂R¹², NR¹²C(O)R¹⁵, NR¹²C(O)OR¹⁵,NR¹²S(O)₂Rl¹⁵, and NR¹²C (O)NHR¹⁵; R¹l is selected from H, halo, —CF₃,—CN, —NO₂, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₄ haloalkyl, C₁₋₆alkoxy, C₃₋₁₀ cycloalkyl, C₃₋₁₀ carbocyclic residue substituted with 0-3R³³, aryl substituted with 0-5 R³³, 5-10 membered heterocyclic ringsystem containing from 1-4 heteroatoms selected from the groupconsisting of N, O, and S substituted with 0-3 R³¹; OR¹², SR¹², NR¹²R¹³,C(O)H, C(O)R¹², C(O)NR¹²R¹³, NR¹⁴C(O)R¹², C(O)OR¹², OC(O)R¹², OC(O)OR¹²,CH(═NR¹⁴)NR¹²R¹³, NHC(═NR¹⁴)NR¹²R¹³, S(O)R¹², S(O)₂R¹², S(O)NR¹²R¹³,S(O)₂NR¹²R¹³, NR¹⁴S(O)R¹², and NR¹⁴S(O)₂R¹²; R¹², at each occurrence, isindependently selected from C₁₄ alkyl substituted with 0-1 R^(12a), C₂₋₄alkenyl substituted with 0-1 R^(12a), C₂₋₄ alkynyl substituted with 0-1R^(12a), C₃₋₆ cycloalkyl substituted with 0-3 R³³, aryl substituted with0-5 R³³; C₃₋₁₀ carbocyclic residue substituted with 0-3 R³³ and 5-10membered heterocyclic ring system containing from 1-4 heteroatomsselected from the group consisting of N, O, and S substituted with 0-3R³¹; R^(12a), at each occurrence, is independently selected from phenylsubstituted with 0-5 R³³; C₃₋₁₀ carbocyclic residue substituted with 0-3R³³, and 5-10 membered heterocyclic ring system containing from 1-4heteroatoms selected from the group consisting of N, O, and Ssubstituted with 0-3 R³¹; R¹³, at each occurrence, is independentlyselected from H, C₁₋₄ alkyl, C₂₋₄ alkenyl, and C₂₋₄ alkynyl;alternatively, R¹² and R¹³ join to form a 5- or 6-membered ringoptionally substituted with —O— or —N(R¹⁴)—; alternatively, R¹² and R¹³when attached to N may be combined to form a 9- or 10-membered bicyclicheterocyclic ring system containing from 1-3 heteroatoms selected fromthe group consisting of N, O, and S, wherein said bicyclic heterocyclicring system is unsaturated or partially saturated, wherein said bicyclicheterocyclic ring system is substituted with 0-3 R¹⁶; R¹⁴, at eachoccurrence, is independently selected from H, methyl, ethyl, propyl, andbutyl; R¹⁵, at each occurrence, is independently selected from H, C₁₋₄alkyl, C₂₋₄ alkenyl, and C₂₋₄ alkynyl; R¹⁶, at each occurrence, isindependently selected from H, OH, F, Cl, CN, NO₂, CF₃, SO₂R⁴⁵, NR⁴⁶R⁴⁷,—C(═O)H, methyl, ethyl, methoxy, ethoxy, trifluoromethyl, andtrifluoromethoxy; R³¹, at each occurrence, is independently selectedfrom H, OH, halo, CF₃, SO₂R⁴⁵, NR⁴⁶R⁴⁷, and C₁₋₄ alkyl; R³³, at eachoccurrence, is independently selected from H, OH, halo, CN, N₂, CF₃,SO₂R⁴⁵, NR⁴⁶R⁴⁷, —C(═O)H, phenyl, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₃₋₆ cycloalkyl, C₁₋₄ haloalkyl, C₁₋₄ haloalkyl-oxy-, C₁₋₄alkyloxy-, C₁₋₄ alkylthio-, C₁₋₄ alkyl-C(═O)—, C₁₋₄ alkyl-C(═O)NH—, C₁₋₄alkyl—OC(═O)—, C₁₋₄ alkyl-C(═O)O—, C₃₋₆ cycloalkyl-oxy-, C₃₋₆cycloalkylmethyl-oxy-; C₁₋₆ alkyl substituted with OH, methoxy, ethoxy,propoxy, butoxy, —SO₂R⁴⁵, —NR⁴⁶R⁴⁷, NR⁴⁶R⁴⁷C(═O)—, or (C₁₋₄ alkyl) CO₂—;and C₂₋₆ alkenyl substituted with OH, methoxy, ethoxy, propoxy, butoxy,—SO₂R⁴⁵, —NR⁴⁶R⁴⁷, NR⁴⁶R⁴⁷C(═O)—, or (C¹⁻⁴ alkyl)CO₂—; R⁴¹, at eachoccurrence, is independently selected from H, CF₃, halo, OH, CO₂H,SO₂R⁴⁵, NR⁴⁶R⁴⁷, NO₂, CN, C₂₋₈ alkenyl, C₂₋₈ alkynyl, C₁₋₄ alkoxy, C₁₋₄haloalkyl C₁₋₄ alkyl substituted with 0-1 R⁴³, aryl substituted with 0-3R⁴², and 5-10 membered heterocyclic ring system containing from 1-4heteroatoms selected from the group consisting of N, O, and Ssubstituted with 0-3 R⁴⁴; R⁴², at each occurrence, is independentlyselected from H, CF₃, halo, OH, CO₂H, SO₂R⁴⁵, NR⁴⁶R⁴⁷, NO₂, CN,CH(═NH)NH₂, NHC(═NH)NH₂, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₄ alkoxy, C₁₋₄haloalkyl, C₃₋₆ cycloalkyl, C₁₋₄ alkyl substituted with 0-1 R⁴³, arylsubstituted with 0-3 R⁴⁴, and 5-10 membered heterocyclic ring systemcontaining from 1-4 heteroatoms selected from the group consisting of N,O, and S substituted with 0-3 R⁴⁴; R⁴³ is C₃₋₆ cycloalkyl or arylsubstituted with 0-3 R⁴⁴; R⁴⁴, at each occurrence, is independentlyselected from H, halo, —OH, NR⁴⁶R⁴⁷, CO₂H, SO₂R⁴⁵, —CF₃, —OCF₃, —CN,—NO₂, C₁₋₄ alkyl, and C₁₋₄ alkoxy; R⁴⁵ is C₁₋₄ alkyl; R⁴⁶, at eachoccurrence, is independently selected from H and C₁₋₄ alkyl; and R⁴⁷, ateach occurrence, is independently selected from H and C₁₋₄ alkyl.
 7. Acompound of claim 5 of formula (I-b):

wherein: X is —CH₂—, —O—, —S—, —CH₂CH₂—, —OCH₂—, or —SCH₂—; R¹ isselected from H, C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, C₃₋₄cycloalkyl, C₁₋₃ alkyl substituted with 0-1 R², C₂₋₃ alkenyl substitutedwith 0-1 R², and C₂₋₃ alkynyl substituted with 0-1 R²; R², at eachoccurrence, is independently selected from C₁₋₄ alkyl, C₂₋₄ alkenyl,C₂₋₄ alkynyl, C₃₋₆ cycloalkyl, phenyl substituted with 0-5 R⁴²; C₃₋₆carbocyclic residue substituted with 0-3 R⁴¹, and 5-6 memberedheterocyclic ring system containing 1, 2, or 3 heteroatoms selected fromthe group consisting of N, O, and S substituted with 0-3 R⁴¹; R^(4a) isH, methyl, ethyl, propyl, or butyl; R^(4b) is H; palternatively, R^(4a)and R^(4b) are taken together to form ═O or ═S; R⁷ and R^(9,) at eachoccurrence, are independently selected from H, halo, —CF₃, —OCF₃, —OH,—CN, —NO₂, —NR⁴⁶R⁴⁷, C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, C₁₋₄haloalkyl, C₁₋₄ alkoxy, (C₁₋₄ haloalkyl)oxy, C₃₋₁₀ cycloalkylsubstituted with 0-2 R³³, C₁₋₄ alkyl substituted with 0-2 R³³, C₃₋₁₀carbocyclic residue substituted with 0-3 R³³, aryl substituted with 0-5R³³, and 5-6 membered heterocyclic ring system containing 1, 2, or 3heteroatoms selected from the group consisting of N, O, and Ssubstituted with 0-3 R³¹; R⁸ is selected from H, halo, —CF₃, —OCF₃, —OH,—CN, —NO₂, C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, C₁₋₄ haloalkyl, C₁₋₄alkoxy, (C₁₋₄ haloalkyl)oxy, C₃₋₁₀ cycloalkyl substituted with 0-2 R³³,C₁₋₄ alkyl substituted with 0-2 R¹¹, C₂₋₄ alkenyl substituted with 0-2R¹¹, C₂₋₄ alkynyl substituted with 0-1 R¹¹, C₃₋₁₀ carbocyclic residuesubstituted with 0-3 R³³, aryl substituted with 0-5 R³³, 5-6 memberedheterocyclic ring system containing 1, 2, or 3 heteroatoms selected fromthe group consisting of N, O, and S substituted with 0-3 R³¹; OR¹²,SR¹², NR¹²R₁₃ NR¹²C(O)R¹⁵, NR¹²C(O)OR¹⁵, NR¹²S(O)₂R¹⁵, andNR¹²C(O)NHR¹⁵; R¹¹ is selected from H, halo, —CF₃, —CN, —NO₂, C₁₋₄alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, C₁₋₄ haloalkyl, C₁₋₄ alkoxy, (C₁₋₄haloalkyl)oxy, C₃₋₁₀ cycloalkyl substituted with 0-2 R³³, C₃₋₁₀carbocyclic residue substituted with 0-3 R³³, aryl substituted with 0-5R³³, and 5-6 membered heterocyclic ring system containing 1, 2, or 3heteroatoms selected from the group consisting of N, O, and Ssubstituted with 0-3 R³¹; R¹², at each occurrence, is independentlyselected from C₁₋₄ alkyl substituted with 0-1 R^(12a), C₂₋₄ alkenylsubstituted with 0-1 R^(12a), C₂₋₄ alkynyl substituted with 0-1 R^(12a),C₃₋₆ cycloalkyl substituted with 0-3 R³³, aryl substituted with 0-5 R³³;C₃₋₁₀ carbocyclic residue substituted with 0-3 R³³, and 5-10 memberedheterocyclic ring system containing from 1-4 heteroatoms selected fromthe group consisting of N, O, and S substituted with 0-3 R³¹; R^(12a),at each occurrence, is independently selected from phenyl substitutedwith 0-5 R³³; C₃₋₁₀ carbocyclic residue substituted with 0-3 R³³, and5-10 membered heterocyclic ring system containing from 1-4 heteroatomsselected from the group consisting of N, O, and S substituted with 0-3R³¹; R¹³, at each occurrence, is independently selected from H, C₁₋₄alkyl, C₂₋₄ alkenyl, and C₂₋₄ alkynyl; alternatively, R¹² and R¹³ jointo form a 5- or 6-membered ring optionally substituted with —O— or—N(R¹⁴)—; alternatively, R¹² and R¹³ when attached to N may be combinedto form a 9- or 10-membered bicyclic heterocyclic ring system containingfrom 1-3 heteroatoms selected from the group consisting of one N, two N,three N, one N one O, and one N one S; wherein said bicyclicheterocyclic ring system is unsaturated or partially saturated, whereinsaid bicyclic heterocyclic ring system is substituted with 0-2 R¹⁶; R¹⁴,at each occurrence, is independently selected from H, methyl, ethyl,propyl, and butyl; R¹⁵, at each occurrence, is independently selectedfrom H, methyl, ethyl, propyl, and butyl; R¹⁶, at each occurrence, isindependently selected from H, OH, F, Cl, CN, NO₂, methyl, ethyl,methoxy, ethoxy, trifluoromethyl, and trifluoromethoxy; R³¹, at eachoccurrence, is independently selected from H, OH, halo, CF₃, methyl,ethyl, and propyl; R³³, at each occurrence, is independently selectedfrom H, OH, halo, CN, NO₂, CF₃, SO₂R⁴⁵, NR⁴⁶R⁴⁷, —C(═O)H, phenyl, C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₆ cycloalkyl, C₁₋₄ haloalkyl, C₁₋₄haloalkyl-oxy-, C₁₋₄ alkyloxy-, C₁₋₄ alkylthio-, C₁₋₄ alkyl-C(═O)—, C₁₋₄alkyl-C(═O)NH—, C₁₋₄ alkyl-OC(═O)—, C₁₋₄ alkyl-C(═O)O—, C₃₋₆cycloalkyl-oxy-, C₃₋₆ cycloalkylmethyl-oxy-; C₁₋₆ alkyl substituted withOH, methoxy, ethoxy, propoxy, butoxy, —SO₂R⁴⁵, —NR⁴⁶R⁴⁷, NR⁴⁶R⁴⁷C(═O)—,or (C₁₋₄ alkyl)CO₂—; and C₂₋₆ alkenyl substituted with OH, methoxy,ethoxy, propoxy, butoxy, —SO₂R⁴⁵, —NR⁴⁶R⁴⁷, NR⁴⁶R⁴⁷C(═O)—, or (C₁₋₄alkyl)CO₂—; R⁴¹, at each occurrence, is independently selected from H,CF₃, halo, OH, CO₂H, SO₂R⁴⁵, NR⁴⁶R⁴⁷, NO₂, CN, C₂₋₄ alkenyl, C₂₋₄alkynyl, C₁₋₃ alkoxy, C₁₋₃ haloalkyl, and C₁₋₃ alkyl; R⁴², at eachoccurrence, is independently selected from H, CF₃, halo, OH, CO₂H,SO₂R⁴⁵, NR⁴⁶R⁴⁷, NO₂, CN, CH(═NH)NH₂, NHC(═NH)NH₂, C₂₋₄ alkenyl, C₂₋₄alkynyl, C₁₋₃ alkoxy, C₁₋₃ haloalkyl, C₃₋₆ cycloalkyl, and C₁₋₃ alkyl;R⁴³ is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, orpyridyl, each substituted with 0-3 R⁴⁴; R⁴⁴, at each occurrence, isindependently selected from H, halo, —OH, NR⁴⁶R⁴⁷, CO₂H, SO₂R⁴⁵, —CF₃,—OCF₃, —CN, —NO₂, methyl, ethyl, propyl, butyl, methoxy, ethoxy,propoxy, and butoxy; R⁴⁵ is methyl, ethyl, propyl, or butyl; R⁴⁶, ateach occurrence, is independently selected from H, methyl, ethyl,propyl, and butyl; and R⁴⁷, at each occurrence, is independentlyselected from from H, methyl, ethyl, propyl, and butyl.
 8. A compound ofclaim 7 wherein: X is —CH₂—, —O— or —S—; R¹ is selected from H, C₁₋₄alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, C₃₋₄ cycloalkyl, C₁₋₃ alkylsubstituted with 0-1 R², C₂₋₃ alkenyl substituted with 0-1 R², and C₂₋₃alkynyl substituted with 0-1 R²; R², at each occurrence, isindependently selected from C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, C₃₋₆cycloalkyl, phenyl substituted with 0-5 R⁴²; C₃₋₆ carbocyclic residuesubstituted with 0-3 R⁴¹, and 5-6 membered heterocyclic ring systemcontaining 1, 2, or 3 heteroatoms selected from the group consisting ofN, O, and S substituted with 0-3 R⁴¹; R^(4a) is H; R^(4b) is H;alternatively, R^(4a) and R^(4b) are taken together to form ═O; R⁷ andR⁹, at each occurrence, are independently selected from H, F, Cl, —CH₃,—OCH₃, —CF₃, —OCF₃, —CN, and —NO₂, R⁸ is selected from H, F, Cl, Br,—CF₃, —OCF₃, —OH, —CN, —NO₂, C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl,C₁₋₄ haloalkyl, C₁₋₄ alkoxy, (C₁₋₄ haloalkyl)oxy, C₃₋₁₀ cycloalkylsubstituted with 0-2 R³³, C₁₋₄ alkyl substituted with 0-2 R¹¹, C₂₋₄alkenyl substituted with 0-2 R¹¹, C₂₋₄ alkynyl substituted with 0-1 R¹¹,C₃₋₁₀ carbocyclic residue substituted with 0-3 R³³, aryl substitutedwith 0-5 R³³, 5-6 membered heterocyclic ring system containing 1, 2, or3 heteroatoms selected from the group consisting of N, O, and Ssubstituted with 0-3 R³¹; OR¹², SR¹², NR¹²R¹³, NR¹²C(O)R¹⁵,NR¹²C(O)OR¹⁵, NR¹²S(O)₂R¹⁵, and NR¹²C(O)NHR¹⁵; R¹¹ is selected from H,halo, —CF₃, —CN, —NO₂, C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, C₁₋₄haloalkyl, C₁₋₄ alkoxy, (C₁₋₄ haloalkyl)oxy, C₃₋₁₀ cycloalkylsubstituted with 0-2 R³³, C₃₋₁₀ carbocyclic residue substituted with 0-3R³³, aryl substituted with 0-5 R³³, and 5-6 membered heterocyclic ringsystem containing 1, 2, or 3 heteroatoms selected from the groupconsisting of N, O, and S substituted with 0-3 R³¹; R¹², at eachoccurrence, is independently selected from C₁₋₄ alkyl substituted with0-1 R^(12a), C₂₋₄ alkenyl substituted with 0-1 R^(12a), C₂₋₄ alkynylsubstituted with 0-1 R^(12a), C₃₋₆ cycloalkyl substituted with 0-3 R³³,aryl substituted with 0-5 R³³; C₃₋₁₀ carbocyclic residue substitutedwith 0-3 R³³, and 5-10 membered heterocyclic ring system containing from1-4 heteroatoms selected from the group consisting of N, O, and Ssubstituted with 0-3 R³¹; R^(12a), at each occurrence, is independentlyselected from phenyl substituted with 0-5 R³³; C₃₋₁₀ carbocyclic residuesubstituted with 0-3 R³³, and 5-10 membered heterocyclic ring systemcontaining from 1-4 heteroatoms selected from the group consisting of N,O, and S substituted with 0-3 R³¹; R¹³, at each occurrence, isindependently selected from H, C₁₋₄ alkyl, C₂₋₄ alkenyl, and C₂₋₄alkynyl; alternatively, R¹² and R¹³ join to form a 5- or 6-membered ringoptionally substituted with —O— or —N(R¹⁴)—; alternatively, R¹² and R¹³when attached to N may be combined to form a 9- or 10-membered bicyclicheterocyclic ring system containing from 1-3 heteroatoms selected fromthe group consisting of N, O, and S; wherein said bicyclic heterocyclicring system is selected from indolyl, indolinyl, indazolyl,benzimidazolyl, benzimidazolinyl, and benztriazolyl; wherein saidbicyclic heterocyclic ring system is substituted with 0-1 R¹⁶; R¹⁴, ateach occurrence, is independently selected from H, methyl, ethyl,propyl, and butyl; R¹⁵, at each occurrence, is independently selectedfrom H, methyl, ethyl, propyl, and butyl; R¹⁶, at each occurrence, isindependently selected from H, OH, F, Cl, CN, NO₂, methyl, ethyl,methoxy, ethoxy, trifluoromethyl, and trifluoromethoxy; R³¹, at eachoccurrence, is independently selected from H, OH, halo, CF₃, methyl,ethyl, and propyl; R³³, at each occurrence, is independently selectedfrom H, OH, halo, CN, NO₂, CF₃, SO₂R⁴⁵, NR⁴⁶R⁴⁷, —C(═O)H, phenyl, C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₆ cycloalkyl, C₁₋₄ haloalkyl, C₁₋₄haloalkyl-oxy-, C₁₋₄ alkyloxy-, C₁₋₄ alkylthio-, C₁₋₄ alkyl-C(═O)—, C₁₋₄alkyl-C(═O)NH—, C₁₋₄ alkyl-OC(═O)—, C₁₋₄ alkyl-C(═O)O—, C₃₋₆cycloalkyl-oxy-, C₃₋₆ cycloalkylmethyl-oxy-; C₁₋₆ alkyl substituted withOH, methoxy, ethoxy, propoxy, butoxy, —SO₂R⁴⁵, —NR⁴⁶R⁴⁷, NR⁴⁶R⁴⁷C(═O)—,or (C₁₋₄ alkyl)CO₂—; and C₂₋₆ alkenyl substituted with OH, methoxy,ethoxy, propoxy, butoxy, —SO₂R⁴⁵, —NR⁴⁶R⁴⁷, NR⁴⁶R⁴⁷C(═O)—, or (C₁₋₄alkyl)CO₂—; R⁴¹, at each occurrence, is independently selected from H,CF₃, halo, OH, CO₂H, SO₂R⁴⁵, NR⁴⁶R⁴⁷, NO₂, CN, C₂₋₄ alkenyl, C₂₋₄alkynyl, C₁₋₃ alkoxy, C₁₋₃ haloalkyl, and C₁₋₃ alkyl; R⁴², at eachoccurrence, is independently selected from H, CF₃, halo, OH, CO₂H,SO₂R⁴⁵, NR⁴⁶R⁴⁷, NO₂, CN, CH(═NH)NH₂, NHC(═NH)NH₂, C₂₋₄ alkenyl, C₂₋₄alkynyl, C₁₋₃ alkoxy, C₁₋₃ haloalkyl, C₃₋₆ cycloalkyl, and C₁₋₃ alkyl;R⁴³ is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, orpyridyl, each substituted with 0-3 R⁴⁴; R⁴⁴, at each occurrence, isindependently selected from H, halo, —OH, NR⁴⁶R⁴⁷, CO₂H, SO₂R⁴⁵, —CF₃,—OCF₃, —CN, —NO₂, methyl, ethyl, propyl, butyl, methoxy, ethoxy,propoxy, and butoxy; R⁴⁵ is methyl, ethyl, propyl, or butyl; R⁴⁶, ateach occurrence, is independently selected from H, methyl, ethyl,propyl, and butyl; and R⁴⁷, at each occurrence, is independentlyselected from from H, methyl, ethyl, propyl, and butyl.
 9. A compound ofclaim 8 wherein: X is —CH₂—, —O—, or —S—; R¹ is selected from H, C₁₋₅alkyl substituted with 0-1 R², C₂₋₅ alkenyl substituted with 0-1 R², andC₂₋₃ alkynyl substituted with 0-1 R²; R² is C₃₋₆ cycloalkyl; R^(4a) isH; R^(4b) is H; R⁷ and R⁹, at each occurrence, are independentlyselected from H, F, Cl, —CH₃, —OCH₃, —CF₃, —OCF₃, —CN, and —NO₂; R⁸ isselected from R¹l; methyl substituted with R¹¹; phenyl substituted with0-2 R³³; OR¹², SR¹², NR¹²R¹³, NR¹²C(O)R¹⁵, NR¹²C(O)OR¹⁵, NR¹²S(O)₂R¹⁵,and NR¹²C(O)NHR¹⁵; R¹¹ is selected from phenyl- substituted with 0-5fluoro; naphthyl- substituted with 0-3 R³³; 2-(H₃CCH₂C(═O))-phenyl-substituted with R³³; 2-(H₃CC(═O))-phenyl- substituted with R³³;2-(HC(═O))-phenyl- substituted with R³³; 2-(H₃CCH(OH))-phenyl-substituted with R³³; 2-(H₃CCH₂CH(OH))-phenyl- substituted with R³³;2-(HOCH₂)-phenyl- substituted with R³³; 2-(HOCH₂CH₂)-phenyl- substitutedwith R³³; 2-(H₃COCH₂)-phenyl- substituted with R³³;2-(H₃COCH₂CH₂)-phenyl- substituted with R³³; 2-(H₃CCH(OMe))-phenyl-substituted with R³³; 2-(H₃COC(═O))-phenyl- substituted with R³³;2-(HOCH₂CH═CH)-phenyl- substituted with R³³; 2-((MeOC═O)CH═CH)-phenyl-substituted with R³³; 2-(methyl)-phenyl- substituted with R³³;2-(ethyl)-phenyl- substituted with R³³; 2-(i-propyl)-phenyl- substitutedwith R³³; 2-(F₃C)-phenyl- substituted with R³³; 2-(NC)-phenyl-substituted with R³³; 2-(H₃CO)-phenyl- substituted with R³³;2-(fluoro)-phenyl- substituted with R³³; 2-(chloro)-phenyl- substitutedwith R³³; 3-(NC)-phenyl- substituted with R³³; 3-(H₃CO)-phenyl-substituted with R³³; 3-(fluoro)-phenyl- substituted with R³³;3-(choro)-phenyl- substituted with R³³; 4-(NC)-phenyl- substituted withR³³; 4-(fluoro)-phenyl- substituted with R³³; 4-(chloro)-phenyl-substituted with R³³; 4-(H₃CS)-phenyl- substituted with R³³;4-(H₃CO)-phenyl- substituted with R³³; 4-(ethoxy)-phenyl- substitutedwith R³³; 4-(i-propoxy)-phenyl- substituted with R³³;4-(i-butoxy)-phenyl- substituted with R³³; 4-(H₃CCH₂CH₂C (═O)) -phenyl-substituted with R³³; 4-((H₃C)₂CHC(═O) ) -phenyl- substituted with R³³;4-(H₃CCH₂C(═O))-phenyl- substituted with R³³; 4-(H₃CC(═O))-phenyl-substituted with R³³; 4-(H₃CCH₂CH₂CH(OH))-phenyl- substituted with R³³;4-((H₃C)₂CHCH(OH))-phenyl- substituted with R³³ ;4-(H₃CCH₂CH(OH))-phenyl- substituted with R³³; 4-(H₃CCH(OH))-phenyl-substituted with R³³; 4-(cyclopropyloxy)-phenyl- substituted with R³³;4-(cyclobutyloxy)-phenyl- substituted with R³³; and4-(cyclopentyloxy)-phenyl- substituted with R³³; R¹² is selected fromphenyl- substituted with 0-5 fluoro; naphthyl- substituted with 0-3 R³³;2-(H₃CCH₂C(═O))-phenyl- substituted with R³³; 2-(H₃CC(═O))-phenyl-substituted with R³³; 2-(HC(═O))-phenyl- substituted with R³³;2-(H₃CCH(OH))-phenyl- substituted with R³³; 2-(H₃CCH₂CH(OH))-phenyl-substituted with R³³; 2-(HOCH₂)-phenyl- substituted with R³³;2-(HOCH₂CH₂)-phenyl- substituted with R³³; 2-(H₃COCH₂)-phenyl-substituted with R³³; 2-(H₃COCH₂CH₂)-phenyl- substituted with R³³;2-(H₃CCH(OMe))-phenyl- substituted with R³³; 2-(H₃COC(═O))-phenyl-substituted with R³³; 2-(HOCH₂CH═CH)-phenyl- substituted with R³³;2-((MeOC═O) CH═CH) -phenyl- substituted with R33; 2-(methyl)-phenyl-substituted with R³³; 2-(ethyl)-phenyl- substituted with R³³;2-(i-propyl)-phenyl- substituted with R³³; 2-(F₃C)-phenyl- substitutedwith R³³; 2-(NC)-phenyl- substituted with R³³; 2-(H₃CO)-phenyl-substituted with R³³; 2-(fluoro)-phenyl- substituted with R³³;2-(chloro)-phenyl- substituted with R³³; 3-(NC)-phenyl- substituted withR³³; 3-(H₃CO)-phenyl- substituted with R³³; 3-(fluoro)-phenyl-substituted with R³³; 3-(chloro)-phenyl- substituted with R³³;4-(NC)-phenyl- substituted with R³³; 4-(fluoro)-phenyl- substituted withR³³; 4-(chloro)-phenyl- substituted with R³³; 4-(H₃CS)-phenyl-substituted with R³³; 4-(H₃CO)-phenyl- substituted with R³³;4-(ethoxy)-phenyl- substituted with R³³; 4-(i-propoxy)-phenyl-substituted with R³³; 4-(i-butoxy)-phenyl- substituted with R³³;4-(H₃CCH₂CH₂C(═))-phenyl- substituted with R³³;4-((H₃C)₂CHC(═O))-phenyl - substituted with R³³; 4-(H₃CCH₂C)(═))-phenyl-substituted with R³³; 4-(H₃CC(═O))-phenyl- substituted with R³³;4-(H₃CCH₂CH₂CH(OH))-phenyl- substituted with R³³;4-((H₃C)₂CHCH(OH))-phenyl- substituted with R³³;4-(H₃CCH₂CH(OH))-phenyl- substituted with R³³; 4-(H₃CCH(OH))-phenyl-substituted with R³³; 4-(cyclopropyloxy)-phenyl- substituted with R³³;4-(cyclobutyloxy)-phenyl- substituted with R³³; and4-(cyclopentyloxy)-phenyl- substituted with R³³; R¹³ is H, methyl, orethyl; alternatively, R¹² and R¹³ join to form a 5- or 6-membered ringselected from pyrrolyl, pyrrolidinyl, imidazolyl, piperidinyl,piperizinyl, methylpiperizinyl,and morpholinyl; alternatively, R¹² andR¹³ when attached to N may be combined to form a 9- or 10-memberedbicyclic heterocyclic ring system containing from 1-3 heteroatomsselected from the group consisting of N, O, and S; wherein said bicyclicheterocyclic ring system is selected from indolyl, indolinyl, indazolyl,benzimidazolyl, benzimidazolinyl, and benztriazolyl; wherein saidbicyclic heterocyclic ring system is substituted with 0-1 R¹⁶; R¹⁵ is H,methyl, ethyl, propyl, or butyl; R¹⁶, at each occurrence, isindependently selected from H, OH, F, Cl, CN, NO₂, methyl, ethyl,methoxy, ethoxy, trifluoromethyl, and trifluoromethoxy; and R³³, at eachoccurrence, is independently selected from H, F, Cl, —CH₃, —OCH₃, —CF₃,—OCF₃, —CN, and —NO₂.
 10. A compound of claim 5 of Formula (I-b):

wherein: R¹ is selected from hydrogen, methyl, ethyl, n-propyl, n-butyl,s-butyl, t-butyl, n-pentyl, n-hexyl, 2-propyl, 2-butyl, 2-pentyl,2-hexyl, 2-methylpropyl, 2-methylbutyl, 2-methylpentyl, 2-ethylbutyl,3-methylpentyl, 3-methylbutyl, 4-methylpentyl, 2-fluoroethyl,2,2-difluoroethyl, 2,2,2-trifluoroethyl, 2-propenyl,2-methyl-2-propenyl, trans-2-butenyl, 3-methyl-butenyl, 3-butenyl,trans-2-pentenyl, cis-2-pentenyl, 4-pentenyl, 4-methyl-3-pentenyl,3,3-dichloro-2-propenyl, trans-3-phenyl-2-propenyl, cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, cyclopropylmethyl,cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, —CH═CH₂,—CH₂—CH═CH₂, —CH═CH—CH₃, —C≡CH, —C≡C—CH₃, and —CH₂—C≡CH; R^(4a) is H;R^(4b) is H; alternatively, R^(4a) and R^(4b) are taken together to form═O; R⁷ and R⁹, at each occurrence, are independently selected fromhydrogen, fluoro, methyl, trifluoromethyl, and methoxy; R⁸ is selectedfrom hydrogen, fluoro, chloro, bromo, cyano, methyl, ethyl, propyl,isopropyl, butyl, t-butyl, nitro, trifluoromethyl, methoxy, ethoxy,isopropoxy, trifluoromethoxy, phenyl, methylC(═O)—, ethylC(═O)—,propylC(═O)—, isopropylC(═O)—, butylC(═O)—, phenylC(═O)—, methylCO₂—,ethylCO₂—, propylCO₂—, isopropylCO₂—, butylCO₂—, phenylCO₂—,dimethylamino-S(═O)—, diethylamino-S(═O)—, dipropylamino-S(═O)—,di-isopropylamino-S(═O)—, dibutylamino-S(═O)—, diphenylamino-S(═O)—,dimethylamino-SO₂—, diethylamino-SO₂—, dipropylamino-SO₂—,di-isopropylamino-SO₂—, dibutylamino-SO₂—, diphenylamino-SO₂—,dimethylamino-C(═O)—, diethylamino-C(═O)—, dipropylamino-C(═O)—,di-isopropylamino-C(═O)—, dibutylamino-C(═O)—, diphenylamino-C(═O)—,2-chlorophenyl, 2-fluorophenyl, 2-bromophenyl, 2-cyanophenyl,2-methylphenyl, 2-trifluoromethylphenyl, 2-methoxyphenyl,2-trifluoromethoxyphenyl, 3-chlorophenyl, 3-fluorophenyl, 3-bromophenyl,3-cyanophenyl, 3-methylphenyl, 3-ethylphenyl, 3-propylphenyl,3-isopropylphenyl, 3-butylphenyl, 3-trifluoromethylphenyl,3-methoxyphenyl, 3-isopropoxyphenyl, 3-trifluoromethoxyphenyl,3-thiomethoxyphenyl, 4-chlorophenyl, 4-fluorophenyl, 4-bromophenyl,4-cyanophenyl, 4-methylphenyl, 4-ethylphenyl, 4-propylphenyl,4-isopropylphenyl, 4-butylphenyl, 4-trifluoromethylphenyl,4-methoxyphenyl, 4-isopropoxyphenyl, 4-trifluoromethoxyphenyl,4-thiomethoxyphenyl, 2,3-dichlorophenyl, 2,3-difluorophenyl,2,3-dimethylphenyl, 2,3-ditrifluoromethylphenyl, 2,3-dimethoxyphenyl,2,3-ditrifluoromethoxyphenyl, 2,4-dichlorophenyl, 2,4-difluorophenyl,2,4-dimethylphenyl, 2,4-ditrifluoromethylphenyl, 2,4-dimethoxyphenyl,2,4-ditrifluoromethoxyphenyl, 2,5-dichlorophenyl, 2,5-difluorophenyl,2,5-dimethylphenyl, 2,5-ditrifluoromethylphenyl, 2,5-dimethoxyphenyl,2,5-ditrifluoromethoxyphenyl, 2,6-dichlorophenyl, 2,6-difluorophenyl,2,6-dimethylphenyl, 2,6-ditrifluoromethylphenyl, 2,6-dimethoxyphenyl,2,6-ditrifluoromethoxyphenyl, 3,4-dichlorophenyl, 3,4-difluorophenyl,3,4-dimethylphenyl, 3,4-ditrifluoromethylphenyl, 3,4-dimethoxyphenyl,3,4-ditrifluoromethoxyphenyl, 2,4,6-trichlorophenyl,2,4,6-trifluorophenyl, 2,4,6-trimethylphenyl ,2,4,6-tritrifluoromethylphenyl, 2,4,6-trimethoxyphenyl,2,4,6-tritrifluoromethoxyphenyl , 2-chloro-4-CF₃-phenyl,2-fluoro-3-chloro-phenyl, 2-chloro-4-CF₃-phenyl,2-chloro-4-methoxy-phenyl, 2-methoxy-4-isopropyl-phenyl,2-CF₃-4-methoxy-phenyl, 2-methyl-4-methoxy-5-fluoro-phenyl,2-methyl-4-methoxy-phenyl, 2-chloro-4-CF₃O-phenyl,2,4,5-trimethyl-phenyl, 2-methyl-4-chloro-phenyl, methyl-C(═O)NH—,ethyl-C(═O)NH—, propyl-C(═O)NH—, isopropyl-C(═O)NH—, butyl-C(═O)NH—,phenyl-C(═O)NH—, 4-acetylphenyl, 3-acetamidophenyl, 4-pyridyl,2-furanyl, 2-thiophenyl, 2-naphthyl; 2-Me-5-F-phenyl, 2-F-5-Me-phenyl,2-MeO-5-F-phenyl, 2-Me-3-Cl-phenyl, 3-NO₂-phenyl, 2-NO₂-phenyl,2-Cl-3-Me-phenyl, 2-Me-4-EtO-phenyl, 2-Me-4-F-phenyl, 2-Cl-6-F-phenyl,2-Cl-4-(CHF₂)O-phenyl, 2,4-diMeO-6-F-phenyl, 2-CF₃-6-F-phenyl,2-MeS-phenyl, 2,6-diCl-4-MeO-phenyl, 2,3,4-triF-phenyl,2,6-diF-4-Cl-phenyl, 2,3,4,6-tetraF-phenyl, 2,3,4,5,6-pentaF-phenyl,2-CF₃-4-EtO-phenyl, 2-CF₃-4-iPrO-phenyl, 2-CF₃-4-Cl-phenyl,2-CF₃-4-F-phenyl, 2-Cl-4-EtO-phenyl, 2-Cl-4-iPrO-phenyl,2-Et-4-MeO-phenyl, 2-CHO-4-MeO-phenyl, 2-CH₃CH(OH)-4-MeO-phenyl,2-CH₃CH(OH)-4-F-phenyl, 2-CH₃CH(OH) -4-Cl-phenyl,2-CH₃CH(OH)-4-Me-phenyl, 2-CH₃CH(OMe)-4-MeO-phenyl,2-CH₃C(═O)-4-MeO-phenyl, 2-CH₃C(═O)-4-F-phenyl, 2-CH₃C(═O)-4-Cl-phenyl,2-CH₃C(═O)-4-Me-phenyl, 2-H₂C(OH)-4-MeO-phenyl, 2-H₂C(OMe)-4-MeO-phenyl,2-H₃CCH₂CH(OH)-4-MeO-phenyl, 2-H₃CCH₂C(═O)-4-MeO-phenyl,2-CH₃CO₂CH₂CH₂-4-MeO-phenyl, (Z)-2-HOCH₂CH═CH-4-MeO-phenyl,(E)-2-HOCH₂CH═CH-4-MeO-phenyl, (Z)-2-CH₃CO₂CH═CH-4-MeO-phenyl,(E)-2-CH₃CO₂CH═CH-4-MeO-phenyl, 2-CH₃OCH₂CH₂-4-MeO-phenyl,2-F-4-MeO-phenyl, 2-Cl-4-F-phenyl, (2-Cl-phenyl)-CH═CH—,(3-Cl-phenyl)—CH═CH—, (2,6-diF-phenyl)-CH═CH—, —CH₂CH═CH₂,phenyl-CH═CH—, (2-Me-4-MeO-phenyl)-CH═CH—, cyclohexyl, cyclopentyl,cyclohexylmethyl, EtCO₂CH₂CH₂—, EtCO₂CH₂CH₂CH₂—, EtCO₂CH₂CH₂CH₂CH₂—,benzyl, 2-F-benzyl, 3-F-benzyl, 4-F-benzyl, 3-MeO-benzyl, 3-OH-benzyl,2-MeO-benzyl, 2-OH-benzyl, 2-MeOC(═O)-3-MeO-phenyl, 2-Me-4-CN-phenyl,2-Me-3-CN-phenyl, 2-Me-4-MeS-phenyl, 2-CF₃-4-CN-phenyl, 2-CHO-phenyl,3-CHO-phenyl, 2-HOCH₂-phenyl, 3-HOCH₂-phenyl, 3-MeOCH₂-phenyl,3-Me₂NCH₂-phenyl, 3-CN-4-F-phenyl, 2-Me-4-H₂NCO-phenyl,2-Me-4-MeOC(═O)-phenyl, 3-H₂NCO-4-F-phenyl, 2-Me₂NCH₂-4-MeO-phenyl-,2-Me-4-CH₃C(═O)-phenyl, phenyl-S—, Me₂N—, 1-pyrrolidinyl, phenyl-NH—,benzyl-NH—, (1-naphthyl)-NH—, (2-naphthyl)-NH—, (2-[1,1′-biphenyl])-NH—,(3-[1,1′-biphenyl])-NH—, (4-[1,1′-biphenyl])-NH—, (2-F-phenyl)-NH—,(2-Cl-phenyl)-NH—, (2-CF₃-phenyl)-NH—, (2-CH₃-phenyl)-NH—,(2-OMe-phenyl)-NH—, (2-CN-phenyl)-NH—, (2-OCF₃-phenyl)-NH—,(2-SMe-phenyl)-NH—, (3-F-phenyl)-NH—, (3-Cl-phenyl)-NH—,(3-CF₃-phenyl)-NH—, (3-CH₃-phenyl)-NH—, (3-OMe-phenyl)-NH—,(3-CN-phenyl)-NH—, (3-OCF₃-phenyl)-NH—, (3-SMe-phenyl)-NH—,(4-F-phenyl)-NH—, (4-Cl-phenyl)-NH—, (4-CF₃-phenyl)-NH—,(4-CH₃-phenyl)-NH—, (4-OMe-phenyl)-NH—, (4-CN-phenyl)-NH—,(4-OCF₃-phenyl)-NH—, (4-SMe-phenyl)-NH—, (2,3-diCl-phenyl)-NH—,(2,4-diCl-phenyl)-NH—, (2,5-diCl-phenyl)-NH—, (2,6-diCl-phenyl)-NH—,(3,4-diCl-phenyl)-NH—, (3,5-diCl-phenyl)-NH—, (2,3-diF-phenyl)-NH—,(2,4-diF-phenyl)-N—, (2,5-diF-phenyl)-NH—, (2,6-diF-phenyl)-NH—,(3,4-diF-phenyl)-NH—, (3,5-diF-phenyl)-NH—, (2,3-diCH₃-phenyl)-NH—,(2,4-diCH₃-phenyl)-NH—, (2,5-diCH₃-phenyl)-NH—, (2,6-diCH₃-phenyl)-NH—,(3,4-diCH₃-phenyl)-NH—, (3,5-diCH₃-phenyl)-NH—, (2,3-diCF₃-phenyl)-NH—,(2,4-diCF₃-phenyl)-NH—, (2,5-diCF₃-phenyl)-NH—, (2,6-diCF₃-phenyl)-NH—,(3,4-diCF₃-phenyl)-NH—, (3,5-diCF₃-phenyl)-NH—, (2,3-diOMe-phenyl)-NH—,(2,4-diOMe-phenyl)-NH—, (2,5-diOMe-phenyl)-NH—, (2,6-diOMe-phenyl)-NH—,(3,4-dioMe-phenyl)-NH—, (3,5-diOMe-phenyl)-NH—, (2-F-3-Cl-phenyl)-NH—,(2-F-4-Cl-phenyl)-NH—, (2-F-5-Cl-phenyl)-NH—, (2-F-6-Cl-phenyl)-NH—,(2-F-3-CH₃-phenyl)-NH—, (2-F-4-CH₃-phenyl)-NH—, (2-F-5-CH₃-phenyl)-NH—,(2-F-6-CH₃-phenyl)-NH—, (2-F-3-CF₃-phenyl)-NH—, (2-F-4-CF₃-phenyl)-NH—,(2-F-5-CF₃-phenyl)-NH—, (2-F-6-CF₃-phenyl)-NH—, (2-F-3-OMe-phenyl)-NH—,(2-F-4-OMe-phenyl)-NH—, (2-F-5-oMe-phenyl)-NH—, (2-F-6-OMe-phenyl)-NH—,(2-Cl-3-F-phenyl)-NH—, (2-Cl-4-F-phenyl)-NH—, (2-Cl-5-F-phenyl)-NH—,(2-Cl-6-F-phenyl)-NH—, (2-Cl-3-CH₃-phenyl)-NH—, (2-Cl-4-CH₃-phenyl)-NH—,(2-Cl-5-CH₃-phenyl)-NH—, (2-Cl-6-CH₃-phenyl)-NH—,(2-Cl-3-CF₃-phenyl)-NH—, (2-Cl-4-CF₃-phenyl)-NH—,(2-Cl-5-CF₃-phenyl)-NH—, (2-Cl-6-CF₃-phenyl)-NH—,(2-Cl-3-OMe-phenyl)-NH—, (2-Cl-4-OMe-phenyl)-NH—,(2-Cl-5-OMe-phenyl)-NH—, (2-Cl-6-OMe-phenyl)-NH—,(2-CH₃-3-F-phenyl)-NH—, (2-CH₃-4-F-phenyl)-NH—, (2-CH₃-5-F-phenyl)-NH—,(2-CH₃-6-F-phenyl)-NH—, (2-CH₃-3-Cl-phenyl)-NH—,(2-CH₃-4-Cl-phenyl)-NH—, (2-CH₃-5-Cl-phenyl)-NH—,(2-CH₃-6-Cl-phenyl)-NH—, (2-CH₃-3-CF₃-phenyl)-NH—,(2-CH₃-4-CF₃-phenyl)-NH—, (2-CH₃-5-CF₃-phenyl)-NH—,(2-CH₃-6-CF₃-phenyl)-NH—, (2-CH₃-3-OMe-phenyl)-NH—,(2-CH₃-4-OMe-phenyl)-NH—, (2-CH₃-5-OMe-phenyl)-NH—,(2-CH₃-6-OMe-phenyl)-NH—, (2-CF₃-3-F-phenyl)-NH—,(2-CF₃-4-F-phenyl)-NH—, (2-CF₃-5-F-phenyl)-NH—, (2-CF₃-6-F-phenyl)-NH—,(2-CF₃-3-Cl-phenyl)-NH—, (2-CF₃-4-Cl-phenyl)-NH—,(2-CF₃-5-Cl-phenyl)-NH—, (2-CF₃-6-Cl-phenyl)-NH—,(2-CF₃-3-CH₃-phenyl)-NH—, (2-CF₃-4-CH₃-phenyl)-NH—,(2-CH₃-5-CF₃-phenyl)-NH—, (2-CF₃-6-CH₃-phenyl)-NH—,(2-CF₃-3-OMe-phenyl)-NH—, (2-CF₃-4-OMe-phenyl)-NH—,(2-CF₃-5-OMe-phenyl)-NH—, (2-CF₃-6-OMe-phenyl)-NH—,(2-OMe-3-F-phenyl)-NH—, (2-OMe-4-F-phenyl)-NH—, (2-OMe-5-F-phenyl)-NH—,(2-OMe-6-F-phenyl)-NH—, (2-OMe-3-Cl-phenyl)-NH—,(2-OMe-4-Cl-phenyl)-NH—, (2-OMe-5-Cl-phenyl)-NH—,(2-OMe-6-Cl-phenyl)-NH—, (2-OMe-3-CH₃-phenyl)-NH—,(2-OMe-4-CH₃-phenyl)-NH—, (2-OMe-5-CH₃-phenyl)-NH—,(2-OMe-6-CH₃-phenyl)-NH—, (2-OMe-3-CF₃-phenyl)-NH—,(2-OMe-4-CF₃-phenyl)-NH—, (2-OMe-5-CF₃-phenyl)-NH—,(2-OMe-6-CF₃-phenyl)-NH— (3- CF₃-4-Cl-phenyl)-NH—,(3-CF₃-4-C(O)CH₃-phenyl)-NH—, (2,3,5-triCl-phenyl)-NH—,(3-CH₃-4-CO₂Me-phenyl)-NH—, and (3-CHO-4-OMe-phenyl)-NH—.
 11. A compoundof formula (I):

or a stereoisomer or a pharmaceutically acceptable salt form thereof,wherein: R¹ is selected from C₁₋₆ alkyl substituted with Z, C₂₋₆ alkenylsubstituted with Z, C₂₋₆ alkynyl substituted with Z, C₃₋₆ cycloalkylsubstituted with Z, aryl substituted with Z, 5-6 membered heterocyclicring system containing at least one heteroatom selected from the groupconsisting of N, O, and S, said heterocyclic ring system substitutedwith Z; C₁₋₆ alkyl substituted with 0-2 R², C₂₋₆ alkenyl substitutedwith 0-2 R², C₂₋₆ alkynyl substituted with 0-2 R², aryl substituted with0-2 R², and 5-6 membered heterocyclic ring system containing at leastone heteroatom selected from the group consisting of N, O, and S, saidheterocyclic ring system substituted with 0-2 R²; Z is selected from H,—CH(OH)R², —C(ethylenedioxy)R², —OR², —SR², —NR²R³, —C(O)R², —C(O)NR²R³,—NR³C(O)R², —C(O)OR², —OC(O)R², —CH(═NR⁴) NR²R³, —NHC(═NR⁴)NR²R³,—S(O)R², —S(O)₂R², —S(O)₂NR²R³, and —NR³S(O)₂R²; R², at each occurrence,is independently selected from C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl,C₃₋₆ cycloalkyl, aryl substituted with 0-5 R⁴²; C₃₋₁₀ carbocyclicresidue substituted with 0-3 R⁴¹, and 5-10 membered heterocyclic ringsystem containing from 1-4 heteroatoms selected from the groupconsisting of N, O, and S substituted with 0-3 R⁴¹; R³, at eachoccurrence, is independently selected from H, C₁₋₄ alkyl, C₂₋₄ alkenyl,C₂₋₄ alkynyl, and C₁₋₄ alkoxy; alternatively, R² and R³ join to form a5- or 6-membered ring optionally substituted with —O— or —N(R⁴)—; R⁴, ateach occurrence, is independently selected from H, methyl, ethyl,propyl, and butyl; R^(4a) is H or C₁₋₄ alkyl; R^(4b) is H;alternatively, R^(4a) and R^(4b) are taken together to form ═O or ═S; R⁵is H or C₁₋₄ alkyl; R⁶ is H or C₁₋₄ alkyl; alternatively, R⁵ and R⁶ aretaken together to form a fused heterocyclic ring of formula:

wherein: X is a bond, —CH₂—, —O—, —S—, —S(═O)—, —S(═O)₂—, —NR¹⁰—,—CH₂CH₂—, —OCH₂—, —SCH₂—, —CH₂O—, —CH₂S—, —CH₂NR¹⁰—, —NR¹⁰CH₂—,—NHC(═O)—, or —C(═O)NH—; and n is 1 or 2; R⁷, R⁸, and R⁹, at eachoccurrence, are independently selected from H, halo, —CF₃, —OCF₃, —OH,—CN, —NO₂, —NR⁴⁶R⁴⁷, C₁₋₈ alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, C₁₋₄haloalkyl, C₁₋₈ alkoxy, (C₁₋₄ haloalkyl)oxy, C₁₋₄ alkyl substituted with0-2 R¹¹, C₃₋₁₀ carbocyclic residue substituted with 0-3 R³³, arylsubstituted with 0-5 R³³, 5-10 membered heterocyclic ring systemcontaining from 1-4 heteroatoms selected from the group consisting of N,O, and S substituted with 0-3 R³¹; OR¹², SR¹², NR¹²R¹³, C(O)H, C(O)R¹²,C(O)NR¹²R¹³, NR¹⁴C(O)R¹², C(O)OR¹², OC(O)R¹², OC(O)OR¹²,CH(═NR¹⁴)NR¹²R¹³, NHC(═NR¹⁴)NR¹²R¹³, S(O)R¹², S(O)₂R¹², S(O)NR¹²R¹³,S(O)₂NR¹²R¹³, NR¹⁴S(O)R¹², NR¹⁴S(O)₂R¹², NR¹²C(O)R¹⁵, NR¹²C(O)OR¹⁵,NR¹²S(O)₂R¹⁵, and NR¹²C(O)NHR¹⁵; R¹⁰ is selected from H, C₁₋₄ alkyl,C₂₋₄ alkenyl, C₂₋₄ alkynyl, and C₁₋₄ alkoxy; R¹¹is selected from H,halo, —CF₃, —CN, —NO₂, C₁₋₈ alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, C₁₋₄haloalkyl, C₁₋₈ alkoxy, C₃₋₁₀ cycloalkyl, C₃₋₁₀ carbocyclic residuesubstituted with 0-3 R³³, aryl substituted with 0-5 R³³, 5-10 memberedheterocyclic ring system containing from 1-4 heteroatoms selected fromthe group consisting of N, O, and S substituted with 0-3 R³¹; OR¹²,SR¹²,NR¹²R¹³, C(O)H, C(O)R¹², C(O)NR¹²R¹³ NR¹⁴C(O)R¹², C(O)OR¹², OC(O)R¹²,OC(O)OR¹², CH(═NR¹⁴)NR¹²R¹³, NHC(═NR¹⁴)NR¹²R¹³, S(O)R¹², S(O)₂R¹²,S(O)NR¹²R¹³, S(O)₂NR¹²R¹³, NR¹⁴S(O)R¹², and NR¹⁴S(O)₂R¹²; R¹², at eachoccurrence, is independently selected from C₁₋₄ alkyl, C₂₋₄ alkenyl,C₂₋₄ alkynyl, C₃₋₆ cycloalkyl, aryl substituted with 0-5 R³³; C₃₋₁₀carbocyclic residue substituted with 0-3 R³³, and 5-10 memberedheterocyclic ring system containing from 1-4 heteroatoms selected fromthe group consisting of N, O, and S substituted with 0-3 R³¹; R¹³, ateach occurrence, is independently selected from H, C₁₋₄ alkyl, C₂₋₄alkenyl, and C₂₋₄ alkynyl; alternatively, R¹² and R¹³ join to form a 5-or 6-membered ring optionally substituted with —O— or —N(R¹⁴)—; R¹⁴, ateach occurrence, is independently selected from H and C₁₋₄ alkyl; R³¹,at each occurrence, is independently selected from H, OH, halo, CF₃,SO₂R⁴⁵, NR⁴⁶R⁴⁷, methyl, ethyl, and propyl; R³³, at each occurrence, isindependently selected from H, OH, halo, CN, NO₂, CF₃, SO₂R⁴⁵, NR⁴⁶R⁴⁷,C₁₋₃ alkyl, C₂₋₃ alkenyl, C₂₋₃ alkynyl, C₃₋₅ cycloalkyl, C₁₋₃ haloalkyl,C₁₋₃ haloalkyl-oxy-, C₁₋₃ alkyloxy-, C₁₋₃ alkylthio-, C₁₋₃ alkyl-C(═O)—,and C₁₋₃ alkyl-C(═O)NH—; R⁴¹, at each occurrence, is independentlyselected from H, CF₃, halo, OH, CO₂H, SO₂R⁴⁵, NR⁴⁶R⁴⁷, NO₂, CN, 50 O,C₂₋₈ alkenyl, C₂₋₈ alkynyl, C₁₋₄ alkoxy, C₁₋₄ haloalkyl C₁₋₄ alkylsubstituted with 0-1 R⁴³, aryl substituted with 0-3 R⁴², and 5-10membered heterocyclic ring system containing from 1-4 heteroatomsselected from the group consisting of N, O, and S substituted with 0-3R⁴⁴; R⁴², at each occurrence, is independently selected from H, CF₃,halo, OH, CO₂H, SO₂R⁴⁵, SR⁴⁵, NR⁴⁶R⁴⁷, OR⁴⁸, NO₂, CN, CH(═NH)NH₂,NHC(═NH)NH₂, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₄ alkoxy, C₁₋₄ haloalkyl,C₃₋₆ cycloalkyl, C₁₋₄ alkyl substituted with 0-1 R⁴³, aryl substitutedwith 0-3 R^(44,) and 5-10 membered heterocyclic ring system containingfrom 1-4 heteroatoms selected from the group consisting of N, O, and Ssubstituted with 0-3 R⁴⁴; R⁴³ is C₃₋₆ cycloalkyl or aryl substitutedwith 0-3 R⁴⁴; R⁴⁴, at each occurrence, is independently selected from H,halo, —OH, NR⁴⁶R⁴⁷, CO₂H, SO₂R⁴⁵, —CF₃, —OCF₃, —CN, —NO₂, C₁₋₄ alkyl,and C₁₋₄ alkoxy; R⁴⁵ is C₁₋₄ alkyl; R⁴⁶, at each occurrence, isindependently selected from H and C₁₋₄ alkyl; R⁴⁷, at each occurrence,is independently selected from H, C₁₋₄ alkyl, —C(═O)NH(C₁₋₄ alkyl),—SO₂(C₁₋₄ alkyl), —SO₂(phenyl), —C(═O)O(C₁₋₄ alkyl), —C(═O) (C₁₋₄alkyl), and —C(═O)H; and R^(48,) at each occurrence, is independentlyselected from H, C₁₋₄ alkyl, —C(═O)NH(C₁₋₄ alkyl), —C(═O)O(C₁₋₄ alkyl),—C(═O) (C₁₋₄ alkyl), and —C(═O)H; provided when R⁵ is H or C₁₋₄ alkyl;and R⁶ is H or C₁₋₄ alkyl; then R¹ is not C₁₋₆ alkyl.
 12. A compound ofclaim 11 wherein: R¹ is selected from ethyl substituted with Z, propylsubstituted with Z, butyl substituted with Z, propenyl substituted withZ, butenyl substituted with Z, ethyl substituted with R², propylsubstituted with R², butyl substituted with R², propenyl substitutedwith R², and butenyl substituted with R²; Z is selected from H,—CH(OH)R², —OR², —SR², —NR²R³, —C(O)R², —C(O)NR²R³, —NR³C(O)R²,—C(O)OR², —S(O)R², —S(O)₂R², —S(O)₂NR²R³, and —NR³S(O)₂R²; R², at eachoccurrence, is independently selected from phenyl substituted with 0-3R⁴²; naphthyl substituted with 0-3 R⁴²; cyclopropyl substituted with 0-3R⁴¹; cyclobutyl substituted with 0-3 R⁴¹; cyclopentyl substituted with0-3 R⁴¹; cyclohexyl substituted with 0-3 R⁴¹; pyridyl substituted with0-3 R⁴¹; indolyl substituted with 0-3 R⁴¹; indolinyl substituted with0-3 R⁴¹; benzimidazolyl substituted with 0-3 R⁴¹; benzotriazolylsubstituted with 0-3 R⁴¹; benzothienyl substituted with 0-3 R⁴¹;benzofuranyl substituted with 0-3 R41; phthalimid-1-yl substituted with0-3 R⁴¹; inden-2-yl substituted with 0-3 R⁴¹; 2,3-dihydro-1H-inden-2-ylsubstituted with 0-3 R⁴¹; indazolyl substituted with 0-3 R⁴¹;tetrahydroquinolinyl substituted with 0-3 R41; andtetrahydro-isoquinolinyl substituted with 0-3 R⁴¹; R³, at eachoccurrence, is independently selected from H, methyl, and ethyl; R^(4a)is H or C₁₋₄ alkyl; R^(4b) is H; alternatively, R^(4a) and R^(4b) aretaken together to form ═O; R⁵ is H or C₁₋₄ alkyl; R⁶ is H or C₁₋₄ alkyl;alternatively, R⁵ and R⁶ are taken together to form a fused heterocyclicring of formula:

wherein: X is —CH₂—, —O—, or —S—; and n is 1; R⁷, R⁸, and R⁹, at eachoccurrence, are independently selected from H, F, Cl, methyl, ethyl,methoxy, —CF₃, and —OCF₃; R⁴¹ at each occurrence, is independentlyselected from H, F, Cl, Br, OH, CF₃, NO₂, CN, ═O, methyl, ethyl, propyl,butyl, methoxy, and ethoxy; R⁴², at each occurrence, is independentlyselected from H, F, Cl, Br, OH, CF₃, SO₂R⁴⁵, SR⁴⁵, NR⁴⁶R⁴⁷ OR₄₈, NO₂,CN, ═O, methyl, ethyl, propyl, butyl, methoxy, and ethoxy; R⁴⁵ ismethyl, ethyl, propyl, or butyl; R⁴⁶, at each occurrence, isindependently selected from H, methyl, ethyl, propyl, and butyl; R⁴⁷, ateach occurrence, is independently selected from H, methyl, ethyl,n-propyl, i-propyl, n-butyl, i-butyl, —C(═O)NH(methyl), —C(═O)NH(ethyl),—SO₂(methyl), —SO₂(ethyl), —SO₂(phenyl), —C(═O)O(methyl),—C(═O)O(ethyl),—C(═O)(methyl), —C(═O)(ethyl), and —C(═O)H; R⁴⁸, at each occurrence, isindependently selected from H, methyl, ethyl, n-propyl, i-propyl,—C(═O)NH(methyl), —C(═O)NH(ethyl), —C(═O)O(methyl), —C(═O)O(ethyl),—C(═O)(methyl), —C(═O)(ethyl), and —C(═O)H.
 13. A compound of claim 11wherein: R¹ is selected from —(CH₂)₃C(═O) (4-fluoro-phenyl),—(CH₂)₃C(═O) (4-bromo-phenyl), —(CH₂)₃C(═O) (4-methyl-phenyl),—(CH₂)₃C(═O) (4-methoxy-phenyl), —(CH₂)₃C(═O)(4-(3,4-dichloro-phenyl)phenyl), —(CH₂)₃C(═O)(3-methyl-4-fluoro-phenyl), —(CH₂)₃C(═O) (2,3-dimethoxy-phenyl),—(CH₂)₃C(═O) (phenyl), —(CH₂)₃C(═O) (4-chloro-phenyl), —(CH₂)₃C(═O)(3-methyl-phenyl), —(CH₂)₃C(═O) (4-t-butyl-phenyl), —(CH₂)₃C(═O)(3,4-difluoro-phenyl), —(CH₂)₃C(═O) (2-methoxy-5-fluoro-phenyl),—(CH₂)₃C(═O) (4-fluoro-1-naphthyl), —(CH₂)₃C(═O) (benzyl), —(CH₂)₃C(═O)(4-pyridyl), —(CH₂)₃C(═O) (3-pyridyl), —(CH₂)₃CH(OH) (4-fluoro-phenyl),—(CH₂)₃CH(OH) (4-pyridyl), —(CH₂)₃CH(OH) (2,3-dimethoxy-phenyl),—(CH₂)₃S(3-fluoro-phenyl), —(CH₂)₃S(4-fluoro-phenyl), —(CH₂)₃S(═O)(4-fluoro-phenyl), —(CH₂)₃SO₂(3-fluoro-phenyl),—(CH₂)₃SO₂(4-fluoro-phenyl), —(CH₂)₃O(4-fluoro-phenyl) —(CH₂)₃O(phenyl),—(CH₂)₃O(3-pyridyl), —(CH₂)₃O(4-pyridyl), —(CH₂)₃O(2-NH₂-phenyl),—(CH₂)₃O(2-NH₂-5-F-phenyl), —(CH₂)₃O(2-NH₂-4-F-phenyl),—(CH₂)₃O(2-NH₂-3-F-phenyl), —(CH₂)₃O(2-NH₂-4-Cl-phenyl),—(CH₂)₃O(2-NH₂-4-OH-phenyl) , —(CH₂)₃O(2-NH₂-4-Br-phenyl),—(CH₂)₃O(2-NHC(═O)Me-4-F-phenyl), —(CH₂)₃O(2 -NHC (═O) Me -phenyl) ,—(CH₂)₃NH(4-fluoro-phenyl) , —(CH₂)₃N(methyl) (4-fluoro-phenyl),—(CH₂)₃CO₂(ethyl), —(CH₂)₃C(═O)N(methyl) (methoxy),—(CH₂)₃C(═O)NH(4-fluoro-phenyl), —(CH₂)₂NHC(═O) (phenyl),—(CH₂)₂NMeC(═O) (phenyl), —(CH₂)₂NHC(═O) (2-fluoro-phenyl),—(CH₂)₂NMeC(═O) (2-fluoro-phenyl), —(CH₂)₂NHC(═O) (4-fluoro-phenyl),—(CH₂)₂NMeC(═O) (4-fluoro-phenyl), —(CH₂)₂NHC(═O) (2,4-difluoro-phenyl),—(CH₂)₂NMeC(═O) (2,4-difluoro-phenyl), —(CH₂)₃(3-indolyl), —(CH₂)₃(1-methyl-3-indolyl), —(CH₂)₃(1-indolyl), —(CH₂)₃(1-indolinyl),—(CH₂)₃(1-benzimidazolyl), —(CH₂)₃(1H-1,2,3-benzotriazol-1-yl),—(CH₂)₃(1H-1,2,3-benzotriazol-2-yl),—(CH₂)₂(1H-1,2,3-benzotriazol-1-yl),—(CH₂)₂(1H-1,2,3-benzotriazol-2-yl), —(CH₂)₃(3,4 dihydro-1(2H)-quinolinyl) , —(CH₂)₂C(═O) (4-fluoro-phenyl),—(CH₂)₂C(═O)NH(4-fluoro-phenyl), —CH₂CH₂(3-indolyl),—CH₂CH₂(1-phthalimidyl), —(CH₂)₄C(═O)N(methyl) (methoxy),—(CH₂)₄CO₂(ethyl), —(CH₂)₄C(═O) (phenyl), —(CH₂)₄(cyclohexyl),—(CH₂)₃CH(phenyl)₂, —CH₂CH₂CH═C(phenyl)₂, —CH₂CH₂CH═CMe(4-F-phenyl),—(CH₂)₃CH(4-fluoro-phenyl)₂, —CH₂CH₂CH═C(4-fluoro-phenyl)₂,—(CH₂)₂(2,3-dihydro-1H-inden-2-yl), —(CH₂)₃C(═O) (2-NH₂-phenyl),—(CH₂)₃C(═O) (2-NH₂-5-F-phenyl), —(CH₂)₃C(═O) (2-NH₂-4-F-phenyl),—(CH₂)₃C(═O) (2-NH₂-3-F-phenyl), —(CH₂)₃C(═O) (2-NH₂-4-Cl-phenyl),—(CH₂)₃C(═O) (2-NH₂-4-OH-phenyl), —(CH₂)₃C(═O) (2-NH₂-4-Br-phenyl),—(CH₂)₃(1H-indazol-3-yl) —(CH₂)₃(5-F-1H-indazol-3-yl),—(CH₂)₃(7-F-1H-indazol-3-yl), —(CH₂)₃(6-1H-indazol-3-yl),—(CH₂)₃(6-Br-1H-indazol-3-yl), —(CH₂)₃(═O) (2NHMe-phenyl),—(CH₂)₃(1-benzothien-3-yl), —(CH₂)₃(6-F-1H-indol-1-yl),—(CH2)₃(5-F-1H-indol-1-yl), —(CH₂)₃(6-F-2,3-dihydro-1H-indol-1-yl),—(CH₂)₃(5-F-2,3-dihydro-1H-indol-1-yl), —(CH₂)₃(6-F-1H-indol-3-yl),—(CH₂)₃(5-F-1H-indol-3-yl), —(CH₂)₃(5-F-1H-indol-3-yl),—(CH₂)₃(9H-purin-9-yl), —(CH₂)₃(7H-purin-7-yl),—(CH₂)₃(6-F-1H-indazol-3-yl), —(CH₂)₃C(═O) (2-NHSO₂Me-4-F-phenyl),—(CH₂)₃C(═O) (2-NHC(═O)Me-4-F-phenyl), —(CH₂)₃C(═O)(2-NHC(═O)Me-phenyl), —(CH₂)₃C(═O) (2-NHCO₂Et-4-F-phenyl), —(CH₂)₃C(═O)(2-NHC(═O)NHEt-4-F-phenyl), —(CH₂)₃C(═O) (2-NHCHO-4-F-phenyl),—(CH₂)₃C(═O) (2-OH-4-F-phenyl), —(CH₂)₃C(═O) (2-MeS-4-F-phenyl),—(CH₂)₃C(═O) (2-NHSO₂Me-4-F-phenyl), —(CH₂)₂C(Me)CO₂Me,—(CH₂)₂C(Me)CH(OH) (4-F-phenyl)₂, —(CH₂)₂C(Me)CH(OH) (4-Cl-phenyl)₂,—(CH₂)₂C(Me)C(═O) (4-F-phenyl), —(CH₂)₂C(Me)C(═O) (2-MeO-4-F-phenyl),—(CH₂)₂C(Me)C(═O) (3-Me-4-F-phenyl), —(CH₂)₂C(Me)C(═O) (2-Me-phenyl),—(CH₂)₂C(Me)C(═O)phenyl,

R^(4a) is H; R^(4b) is H; alternatively, R^(4a) and R^(4b) are takentogether to form ═O; R⁵ is H, methyl, ethyl, propyl, or butyl; R⁶ is H,methyl, ethyl, propyl, or butyl; alternatively, R⁵ and R⁶ are takentogether to form a fused heterocyclic ring of formula:

wherein: X is —CH₂—, —O—, or —S—; and n is 1; R⁷, R⁸, and R⁹, at eachoccurrence, are independently selected from hydrogen, fluoro, chloro,bromo, cyano, methyl, ethyl, propyl, isopropyl, butyl, t-butyl, nitro,trifluoromethyl, methoxy, ethoxy, isopropoxy, trifluoromethoxy, phenyl,benzyl, HC(═O)—, methylC(═O)—, ethylC(═O)—, propylC(═O)—,isopropylC(═O)—, n-butylC(═O)—, isobutylC(═O)—, secbutylC(═O)—,tertbutylC(═O)—, phenylC(═O)—, methylC(═O)NH—, ethylC(═O)NH—,propylC(═O)NH—, isopropylC(═O)NH—, n-butylC(═O)NH—, isobutylC(═O)NH—,secbutylC(═O)NH—, tertbutylC(═O)NH—, phenylC(═O)NH—, methylamino-,ethylamino-, propylamino-, isopropylamino-, n-butylamino-,isobutylamino-, secbutylamino-, tertbutylamino-, phenylamino-, providedthat two of substituents R⁷, R⁸, and R⁹, are independently selected fromhydrogen, fluoro, chloro, bromo, cyano, methyl, ethyl, propyl,isopropyl, butyl, t-butyl, nitro, trifluoromethyl, methoxy, ethoxy,isopropoxy, and trifluoromethoxy.
 14. A pharmaceutical compositioncomprising a pharmaceutically acceptable carrier and a therapeuticallyeffective amount of a compound of claim 1, or a pharmaceuticallyacceptable salt thereof.
 15. A pharmaceutical composition comprising apharmaceutically acceptable carrier and a therapeutically effectiveamount of a compound of claim 11, or a pharmaceutically acceptable saltthereof.
 16. A method for treating a human suffering from a disorderassociated with 5HT2C receptor modulation comprising administering to apatient in need thereof a therapeutically effective amount of a compoundof claim 1, or a pharmaceutically acceptable salt thereof.
 17. A methodof claim 16 for treating a human suffering from a disorder associatedwith 5HT2C receptor modulation wherein the compound is a 5HT2C agonist.18. A method for treating a human suffering from a disorder associatedwith 5HT2A receptor modulation comprising administering to a patient inneed thereof a therapeutically effective amount of a compound of claim11, or a pharmaceutically acceptable salt thereof.
 19. A method of claim18 for treating a human suffering from a disorder associated with 5HT2Areceptor modulation wherein the compound is a 5HT2A antagonist.
 20. Amethod for treating obesity comprising administering to a patient inneed thereof a therapeutically effective amount of a compound of claim1, or a pharmaceutically acceptable salt thereof.
 21. A method fortreating schizophrenia comprising administering to a patient in needthereof a therapeutically effective amount of a compound of claim 11, ora pharmaceutically acceptable salt thereof.
 22. A method for treatingdepression comprising administering to a patient in need thereof atherapeutically effective amount of a compound of claim 11, or apharmaceutically acceptable salt thereof.